Mesenchymal Stromal Cells: Bridging the Gaps in Hematologic Disease Therapy.

Introduction

Hematologic diseases encompass a heterogeneous spectrum of malignant and non-malignant disorders, including leukemias, lymphomas, bone marrow failure syndromes, and immune-mediated conditions [ 1 – 3 ]. Despite substantial advancements in chemotherapy, targeted therapies, hematopoietic stem cell transplantation (HSCT), and immunotherapy, many hematologic diseases remain challenging to treat. For instance, while the 5-year survival rate for younger patients with acute myeloid leukemia (AML) has improved from 13% in the 1970 s to approximately 55% in the modern era because of optimized chemotherapy and transplantation protocols [ 4 ], relapse, resistance, and treatment-related toxicities continue to adversely affect long-term outcomes [ 4 – 7 ]. Additionally, the high cost of emerging therapies, including chimeric antigen receptor (CAR)-T cell therapy and gene therapy, pose significant challenges in terms of accessibility, particularly in resource-constrained settings [ 8 , 9 ].

Against this backdrop, mesenchymal stromal cells (MSCs) have emerged as a promising avenue in hematologic disease therapy. Unlike hematopoietic stem cells (HSCs), which primarily restore blood cell production, MSCs exert supportive and regulatory functions by sustaining the hematopoietic niche and modulating immune responses [ 10 ]. This dual role, distinct from the targeted cytotoxicity of immune cell therapies such as CAR-T cells, underlies their therapeutic relevance, particularly in transplantation-related complications [ 11 ].

MSCs were first identified in bone marrow in 1966 by Friedenstein as clonogenic fibroblast-like cells with osteogenic and chondrogenic potential [ 12 ]. In 2006, the International Society for Cellular Therapy (ISCT) proposed minimal criteria to standardize their definition [ 13 ]. These criteria include adherence to plastic under conventional culture conditions, a characteristic immunophenotype defined by expression of CD73, CD90, and CD105 with the absence of hematopoietic and immune markers such as CD34, CD45, CD14/CD11b, CD79a/CD19, and HLA-DR, and the capacity to differentiate in vitro into osteoblasts, adipocytes, and chondroblasts [ 13 ].

Beyond these defining features, MSCs integrate immunomodulation, hematopoietic support, and tissue repair into a multifaceted therapeutic profile [ 14 – 16 ]. They can be derived from various tissue sources [ 17 ], enabling scalable and potentially allogeneic applications. Emerging approaches such as MSC-derived extracellular vesicles (EVs) and engineered MSCs further expand therapeutic opportunities [ 8 ].

Nevertheless, clinical translation faces persistent obstacles, including variability in therapeutic efficacy, concerns regarding pro-tumorigenic effects, and the need for standardized manufacturing and delivery protocols [ 18 ]. Despite promising preclinical and early-phase clinical data, unresolved questions regarding optimal sources, dosing strategies, and mechanisms of interaction with hematopoietic and malignant cells highlight the need for rigorous translational research.

This review critically examines the therapeutic role of MSCs in hematologic diseases, integrating insights from recent preclinical and clinical studies. By elucidating their mechanisms of action, therapeutic potential, and translational challenges, we aim to provide a comprehensive perspective on their potential and the key priorities for optimizing MSC-based strategies in the field of hematology.

Sources of MSCs

MSCs are derived from a wide range of tissues, including bone marrow, umbilical cord, adipose tissue, and other emerging sources. Their biological characteristics differ across origins, shaping therapeutic applicability in hematologic diseases (Table 1 ).

Bone marrow–derived MSCs (BM-MSCs) remain the most extensively investigated population due to their immunomodulatory capacity and ability to sustain hematopoiesis [ 37 , 38 ]. They have been shown to enhance HSCT outcomes, mitigate GVHD, and support recovery in bone marrow failure syndromes [ 19 – 22 ]. Their clinical utility, however, is restricted by invasive harvesting, low cell yield, and donor-to-donor variability. These limitations have encouraged exploration of alternative sources with greater scalability and consistency.

Umbilical cord–derived MSCs (UC-MSCs) provide several advantages, including non-invasive procurement, high proliferative potential, and low immunogenicity [ 17 , 23 – 25 ]. These features facilitate allogeneic use in HSCT and immune-related disorders such as GVHD, aplastic anemia (AA), and immune thrombocytopenia (ITP) [ 25 , 39 – 45 ]. UC-MSCs promote immune tolerance by releasing chemokines that recruit suppressor cells, thereby reducing T cell activation and inflammatory cytokine secretion [ 46 ]. Preconditioning approaches, such as hypoxic culture, further enhance their immunosuppressive effects by favoring regulatory T cell (Treg) responses [ 47 ]. Their utility also extends to gene delivery and regenerative applications [ 17 , 48 , 49 ]. Despite these benefits, reports of complications such as disseminated intravascular coagulation at high doses emphasize the need for standardized administration protocols [ 50 ].

Within the umbilical cord, Wharton’s Jelly (WJ-MSCs) provides a rich source of MSCs that can be isolated non-invasively from tissue normally discarded after birth, thereby avoiding donor risk and ethical concerns [ 51 , 52 ]. Compared with adult MSCs, WJ-MSCs proliferate more rapidly, expand for longer periods in vitro, and maintain greater genomic stability [ 51 , 53 ]. They also express transcription factors associated with developmental immaturity and exhibit an immunological profile characterized by reduced HLA class I expression and secretion of tolerogenic mediators [ 51 – 54 ]. These features support immune compatibility and reduce the risk of rejection [ 52 , 54 ]. Preclinical and early clinical studies indicate their capacity to modulate alloimmune responses in transplantation settings [ 51 , 52 , 54 ].

Adipose tissue–derived MSCs (AD-MSCs) are abundant and easily accessible. They display strong proliferative and anti-inflammatory properties [ 55 ]. Preclinical work suggests their ability to promote hematopoietic recovery and modulate immune responses in GVHD and chemotherapy-induced marrow injury [ 26 , 27 ]. Nevertheless, donor-related heterogeneity remains a significant challenge [ 55 ].

Pluripotent stem cells, including human embryonic stem cells (hESCs) and induced pluripotent stem cells (hiPSCs), represent another source. MSC-like cells generated from hiPSCs are referred to as induced MSCs (iMSCs) [ 28 ]. These cells offer virtually unlimited expansion capacity and improved genetic consistency compared with adult MSCs [ 29 – 31 ]. Their scalability supports standardized, off-the-shelf manufacturing [ 29 , 30 ]. Preclinical studies demonstrate immunomodulatory and hematopoietic-supportive effects comparable, and sometimes superior, to those of adult MSCs [ 28 , 29 ]. Ongoing clinical trials are evaluating their safety and efficacy, including a Phase I study in steroid-refractory GVHD ( NCT06321198 ) and a Phase II trial of a Cymerus-derived product in high-risk GVHD ( NCT05643638 ). Several biotechnology companies, including Cynata Therapeutics and Fujifilm Cellular Dynamics, are developing iMSC products, reflecting the increasing focus on this next-generation MSC source.

In addition to established sources, emerging tissue origins provide new therapeutic potential, particularly in immune regulation and hematopoietic support [ 56 ]. Placenta-derived MSCs modulate the Th17/Tr1 balance through PD-L2 expression, suggesting a role in GVHD management [ 32 ]. Amniotic membrane–derived MSCs exert immunosuppressive activity via PD-L1 upregulation and may hold promise for cytokine release syndrome and immune-related complications [ 33 , 34 ]. Gingiva-derived MSCs (G-MSCs) stabilize Tregs through CD39 signaling, preventing conversion to pro-inflammatory phenotypes while preserving Foxp3 expression, thereby supporting Treg-mediated suppression [ 35 , 36 ]. Compared with BM-MSCs and AD-MSCs, G-MSCs show higher proliferation and stronger immunomodulation, highlighting their relevance in GVHD therapy [ 36 ]. These sources remain under investigation, and further work is required to establish standardized protocols and comparative efficacy.

In summary, the therapeutic potential of MSCs is strongly influenced by their tissue of origin. BM-MSCs provide robust hematopoietic support but are constrained by limited yield and donor variability [ 19 – 22 ]. UC- and WJ-MSCs combine scalability with immune tolerance, favoring allogeneic applications [ 17 , 23 – 25 , 51 , 52 ]. AD-MSCs are abundant but heterogeneous [ 26 , 27 ]. iMSCs derived from pluripotent cells offer scalability and genetic stability, representing a next-generation alternative [ 28 – 31 ]. Placenta-, amnion-, and gingiva-derived MSCs expand the range of available sources, although further validation is necessary [ 32 – 36 ]. The origin of MSCs therefore plays a critical role in shaping their immunological profile, hematopoietic support, and translational feasibility in hematologic disorders.

Mechanisms of MSC Action in Hematologic Disorders

Immunomodulation

MSCs are recognized for their capacity to regulate both innate and adaptive immune cells, which underlies their therapeutic value in immune-mediated hematologic disorders, including GVHD, AA, and ITP [ 19 , 57 – 61 ]. These effects are achieved through modulation of cytokine networks, alteration of immune cell function, and reprogramming of metabolic pathways.

A central feature of MSC-mediated immunoregulation is the establishment of an anti-inflammatory microenvironment. This is accomplished through the secretion of IL-10, TGF-β, prostaglandin E2 (PGE2), and indoleamine 2,3-dioxygenase (IDO). These mediators suppress inflammatory cascades and attenuate the production of IFN-γ, TNF-α, and IL-6 [ 40 , 62 , 63 ]. Such a cytokine shift prevents excessive immune activation, tissue injury, and immune rejection. Importantly, MSCs adapt their immunoregulatory activity to the inflammatory context. During acute inflammation, secretion of CXCL1 and CXCL12 promotes immune cell recruitment to sites of injury, facilitating resolution and repair [ 46 ]. Under chronic inflammatory conditions, MSCs suppress infiltration by downregulating chemokines such as CCL1 and CCL3 and their receptors CCR4 and CCR8. This modulation restricts T cell and macrophage trafficking into the skin, thereby mitigating inflammation-induced fibrosis [ 64 ].

MSCs also regulate T cell subsets. PGE2- and IDO-dependent pathways inhibit Th1 and Th17 differentiation, while TGF-β and IDO-1 reduce T cell activation and promote senescence, leading to stabilization of Tregs [ 65 ] (Fig. 1 ). Moreover, MSC-derived extracellular vesicles (EVs) carry immunoregulatory miRNAs, including miR-222-3p and miR-146a-5p [ 19 , 58 , 62 , 66 – 68 ].

Beyond T cells, MSCs exert broad influence on other immune populations. MSC-derived PGE2 and TGF-β suppress B cell proliferation and antibody secretion (Fig. 2 A), thereby reducing autoantibody-mediated pathology in ITP [ 69 ]. In macrophages, MSCs drive polarization from the pro-inflammatory M1 phenotype to the anti-inflammatory M2 phenotype, mainly through TGF-β and IL-10 signaling via the PI3K/Akt pathway [ 67 ] (Fig. 2 C). This transition alleviates inflammatory injury in GVHD and ITP. MSCs also enhance neutrophil survival and phagocytosis through secretion of granulocyte colony-stimulating factor and IL-10, an effect particularly relevant in congenital neutropenia [ 70 , 71 ] (Fig. 2 B). In parallel, MSCs suppress NK cell cytotoxicity by downregulating activating receptors such as NKG2D (Fig. 2 D), and they impair dendritic cell maturation and antigen presentation through TGF-β and PGE2 signaling [ 67 ] (Fig. 2 E).

In addition to direct cellular interactions, MSCs reprogram the metabolic profile of immune responses by altering glycolytic and oxidative phosphorylation (OXPHOS) pathways [ 63 ]. This metabolic modulation restores immune balance and supports hematopoietic homeostasis. However, because MSCs can also suppress anti-leukemic immunity, further studies are needed to weigh their therapeutic benefits against potential risks in hematologic malignancies.

Hematopoietic Support

MSCs are essential for hematopoiesis because they regulate the bone marrow microenvironment and maintain hematopoietic stem cell (HSC) function [ 27 ]. Support for HSCs is provided through both paracrine signaling and direct cell-to-cell interactions. MSCs secrete hematopoietic cytokines and growth factors, including CXCL12, CXCL8, stem cell factor (SCF), hepatocyte growth factor (HGF), angiopoietin-1 (ANG-1), and vascular endothelial growth factor (VEGF). These molecules sustain HSC survival, proliferation, homing, and lineage differentiation [ 40 , 72 ].

In addition to soluble mediators, extracellular vesicle (EV)-dependent mechanisms contribute to hematopoietic recovery. MSC-derived EVs contain regulatory miRNAs, such as miR-23a-3p and miR-146a-5p , that promote HSC quiescence, protect against oxidative injury, and enhance immune tolerance [ 62 ]. MSCs also transfer mitochondria to hematopoietic progenitors, which enhances oxidative phosphorylation (OXPHOS), reduces oxidative stress, and maintains metabolic fitness [ 73 ]. This process limits apoptosis and promotes hematopoietic regeneration after bone marrow injury [ 73 ]. However, mitochondrial transfer between MSCs and hematopoietic stem and progenitor cells (HSPCs) primarily occurs under stress conditions, such as irradiation, chemotherapy, leukemic infiltration, or inflammatory injury. Evidence indicates that, under steady-state hematopoiesis, mitochondrial transfer is minimal or negligible [ 74 – 76 ]. Despite strong associations between mitochondrial uptake and improved metabolic activity, causality remains uncertain. Inhibition strategies that block tunneling nanotube formation also interfere with adhesion and signaling, complicating interpretation. Thus, mitochondrial transfer is best regarded as an adaptive mechanism that facilitates hematopoietic restoration under stress, although its therapeutic relevance requires further study.

Anti-Fibrosis Effects and Tissue Repair

MSCs counteract fibrosis and support tissue repair by modulating fibrotic pathways, remodeling the extracellular matrix (ECM), and restoring microenvironmental homeostasis [ 57 , 77 ] (Fig. 3 A). Fibrosis results from excessive ECM accumulation driven by persistent TGF-β/Smad signaling [ 78 ]. This pathway is suppressed by MSCs, leading to reduced collagen synthesis and ECM deposition [ 64 ].

Concurrently, MSC-secreted matrix metalloproteinases (e.g., MMP-1) degrade fibrotic ECM, facilitating tissue remodeling [ 64 ]. MSC-derived hepatocyte growth factor (HGF) and VEGF enhance vascular integrity and oxygen delivery, thereby alleviating hypoxia-induced fibrotic damage [ 77 , 79 ]. EVs further amplify these effects by delivering miRNAs (e.g., miR-146a-5p , miR-23a-3p , miR-124-5p ) that regulate fibrosis-associated gene expression [ 77 ].

By limiting fibrosis, MSCs create conditions favorable for tissue regeneration. Regenerative processes are also enhanced directly through metabolic reprogramming and paracrine signaling (Fig. 3 B). Under stress conditions, MSCs activate hypoxia-inducible factor 1-alpha (HIF1α) and IDO pathways, which reduce oxidative damage, support metabolic adaptation, and accelerate cellular repair [ 80 ]. In addition, MSC-derived CXCL12, SCF, and IL-6 reinforce the hematopoietic niche and facilitate bone marrow recovery [ 80 ].

MSCs also transfer mitochondria to injured cells, restoring bioenergetics, reducing oxidative stress, and enhancing regeneration after tissue injury [ 81 ]. EVs contribute by modulating metabolic pathways, while angiogenic factors secreted by MSCs, such as VEGF, HGF, stromal-derived factor-1 (SDF-1), and basic fibroblast growth factor (bFGF), promote neovascularization and stromal remodeling [ 82 , 83 ].

MSCs in Hematologic Malignancies: A Double-Edged Sword

MSCs display paradoxical effects in hematologic malignancies through mechanisms shaped by leukemia subtype, cytokine milieu, and responding cell type [ 84 ]. In some contexts, they induce apoptosis, restrain proliferation, and modulate immune responses [ 85 ]. In others, they remodel the bone marrow niche, enhance chemoresistance, and facilitate immune evasion, thereby accelerating disease progression [ 86 , 87 ]. Clarifying the molecular basis of this duality is critical for the rational design of MSC-based therapeutic strategies.

Anti-tumor activity of MSCs is mediated mainly through paracrine signaling and extracellular vesicles (EVs) (Fig. 4 A). EVs deliver regulatory miRNAs such as miR-7-5p , miR-124-5p , and miR-23b-5p [ 66 , 88 – 93 ]. These molecules promote apoptosis by upregulating p53 and BAX while suppressing BCL-2 [ 94 ]. In AML, miR-7-5p downregulates OSBPL11, inhibiting the PI3K/AKT/mTOR pathway and limiting leukemic proliferation [ 89 ]. MSC-derived EVs also disrupt redox balance in tumor cells, amplifying apoptotic signaling [ 94 ]. In addition, MSCs can be engineered as therapeutic carriers; for example, TRAIL-expressing MSCs inhibit PI3K/AKT and MEK/ERK cascades and induce apoptosis in ALL cells [ 49 ].

In contrast, malignant cells can reprogram MSCs into tumor-supportive phenotypes [ 18 , 95 , 96 ] (Fig. 4 B). Under pathological stress, MSCs shift their secretome toward pro-tumorigenic factors, including IL-6, IL-17 A, CXCL8, CXCL12, and periostin [ 97 – 101 ]. These molecules activate oncogenic signaling cascades such as JAK2/STAT3, PI3K/AKT, SDF-1/CXCR4, TGF-β, NF-κB, and LTβR [ 97 , 99 , 100 , 102 – 110 ]. In AML and ALL, leukemia-derived LTα1β2 activates LTβR in MSCs, suppressing IL-7 production, impairing lymphopoiesis, and providing leukemic cells with a competitive advantage [ 102 ]. CXCR4 signaling further enhances LTα1β2 secretion, reinforcing leukemic survival [ 102 ]. Inhibition of LTβR signaling restores hematopoiesis and limits leukemic expansion [ 102 ]. MSCs also contribute to tumor progression by regulating ECM remodeling through the secretion of matrix metalloproteinases (e.g., MMP-9), facilitating tumor invasion and dissemination [ 111 ]. Additionally, MSCs reshape the immune microenvironment by polarizing macrophages toward the M2 phenotype, supporting the expansion of tumor-associated macrophages (TAMs) that promote angiogenesis and immune suppression [ 112 – 114 ]. Concomitantly, MSCs inhibit anti-tumor immune responses by suppressing NK cell cytotoxicity through the TIGIT/CD155 axis and attenuating T cell activity via PD-1/PD-L1 interactions [ 115 , 116 ]. Notably, patient-derived MSCs display enhanced immunosuppressive capacity, further weakening immune surveillance [ 117 ]. At the metabolic level, MSCs transfer tumor-supportive miRNAs such as miR-26a-5p and miR-155 , activating Wnt/β-catenin, PI3K/AKT/mTOR, and ERK pathways [ 14 , 87 , 118 , 119 ]. In AML, mitochondrial transfer from MSCs sustains OXPHOS, enabling leukemic cells to tolerate metabolic stress and adopt a therapy-resistant state [ 74 ]. Moreover, MSCs undergo cancer-associated fibroblast (CAF)-like reprogramming, characterized by secretion of IL-6, CXCL12, and TGF-β [ 120 , 121 ], together with a shift from osteogenic toward adipogenic and fibrotic differentiation, which destabilizes the hematopoietic niche and favors leukemic persistence [ 106 , 122 – 125 ].

The functional heterogeneity of MSCs depends on their origin and disease context. MSCs derived from healthy donors, such as umbilical cord or normal bone marrow, generally preserve niche integrity and immune surveillance [ 126 ], whereas patient-derived MSCs or those remodeled by leukemic blasts acquire tumor-promoting features [ 86 ]. Stromal reprogramming also varies across disease subtypes: AML and ALL show distinct expression of regulators such as IL-7 and Lama4 [ 127 , 128 ]. The cytokine milieu plays a critical role; elevated IL-6 and CXCL12 promote tumor-supportive activity [ 129 , 130 ], whereas IL-7 supports lymphopoiesis and tumor suppression [ 131 ]. Functional outcomes also differ according to the responding cell type, including hematopoietic progenitors, immune effectors, or leukemic stem cells [ 79 ]. Stress conditions such as chemotherapy, radiotherapy, or inflammation markedly enhance the tumor-supportive functions of MSCs [ 132 ], whereas under steady-state hematopoiesis their impact on malignant progression appears limited [ 133 , 134 ].

These findings emphasize the complexity of MSC biology in leukemia. MSCs can serve as vehicles for tumor-suppressive miRNAs or engineered therapeutic molecules, yet their plasticity allows malignant reprogramming that promotes drug resistance and immune escape. Strategies targeting tumor-promoting pathways such as LTβR or CXCL12/CXCR4, or employing genetic engineering, may enable exploitation of their therapeutic value while limiting adverse effects.

Potential and Emerging Therapeutic Roles of MSCs in Hematologic Diseases

GVHD

Therapeutic Applications of MSCs in GVHD

MSCs attenuate GVHD symptoms through modulation of the IFN-γ/IL-6 pathway, leading to reduced T cell hyperactivation and systemic inflammation [ 135 ]. Recent investigations indicate that MSCs also influence metabolic regulation. Activation of the CREB1–NRF2 axis enhances glutathione (GSH) metabolism, which sustains antioxidant capacity and suppresses T cell activation [ 136 ]. Preconditioning strategies, including hypoxic culture and exposure to vitamin C derivatives or valproic acid, further strengthen therapeutic efficacy by upregulating genes associated with glutathione metabolism [ 137 ]. MSC-derived extracellular vesicles (EVs) display additional immunoregulatory activity by transferring bioactive molecules such as miRNAs and proteins. For instance, exosomal miR-223 targets ICAM-1, thereby restricting donor T cell migration and limiting tissue infiltration in affected organs [ 68 ].

Clinical studies demonstrate efficacy in both acute and chronic GVHD (Table 2 ). Several trials report high response rates, and products such as Temcell and UC-MSCs have induced remission in pediatric and adult cohorts [ 60 , 149 ]. Regulatory approvals have been granted for multiple MSC-based products (Table 3 ) [ 158 ]. Notably, Ryoncil (remestemcel-L-rknd) received FDA approval in December 2024 for steroid-refractory aGVHD, marking an important milestone in clinical application. Optimized strategies are being tested: MSC pre-infusion lowers the incidence of grade II–IV aGVHD in haploidentical transplant recipients [ 155 ], and repeated infusions improve inflammatory markers and patient-reported outcomes in chronic GVHD [ 20 ].

Promising results have also been reported in high-risk populations, such as severe pediatric GVHD [ 150 ]. Although enhanced remission and survival rates have been observed, uncertainties remain regarding dosing regimens and long-term durability of responses [ 140 ]. Large-scale randomized trials are needed to confirm efficacy and establish standardized treatment protocols.

Challenges in MSC-Based GVHD Therapy

The clinical translation of MSC therapy faces persistent challenges, including efficacy variability, heterogeneous trial designs, patient-specific influences, and safety considerations. Differences in donor origin, cellular characteristics, and manufacturing protocols contribute to therapeutic inconsistency. MSCs derived from younger donors (≤ 35 years) generally demonstrate greater potency than those from older donors [ 148 ]. Molecular analyses further suggest that elevated expression of IDO1 and TGF-β enhances immunomodulatory activity. However, variation in trial design—such as MSC source, processing methods, and administration schedules—hinders direct cross-study comparison [ 159 , 160 ].

Ex vivo expansion, commonly required for clinical applications, may alter MSC phenotype and function relative to freshly isolated stromal cells. Qian et al. reported that expanded MSCs exhibit modified surface marker expression, reduced homing receptor levels, and altered secretory patterns, potentially resulting in unpredictable biodistribution and variable in vivo activity [ 161 ].

Patient-related factors also shape therapeutic outcomes. HLA-G expression and HLA-G polymorphisms, for instance, significantly influence treatment efficacy. High expression correlates with enhanced immunomodulation, while specific polymorphisms contribute to variable clinical responses [ 16 ]. Incorporating genetic profiling may facilitate personalized approaches and improve therapeutic consistency.

Safety remains a concern in immunocompromised populations. Although MSCs are generally well tolerated, increased risks of infection and suboptimal survival have been documented in certain GVHD subtypes [ 139 , 142 ]. The immunosuppressive milieu induced by MSC therapy may, in some cases, exacerbate infection susceptibility [ 139 ].

Optimization Strategies for MSC-Based GVHD Therapy

Enhancing the functionality of MSCs is essential to reduce therapeutic variability. Genetic modification and cellular preconditioning have yielded encouraging results. AKT1 modification, for example, increases MSC viability in inflammatory environments and attenuates immune responses in acute hepatic GVHD [ 162 ]. Metabolic reprogramming of UC-MSCs strengthens their capacity to inhibit T cell proliferation and promote Treg differentiation [ 24 ]. These modified MSCs preserve biological function after cryopreservation, allowing long-term storage and use [ 24 ]. Hypoxic preconditioning improves stemness, delays senescence, and augments immunomodulatory properties [ 47 , 163 ]. Preconditioning with plasma from GVHD patients further enhances immunoregulatory capacity [ 164 ], underscoring the relevance of tailoring MSCs to specific pathological contexts.

MSC-derived extracellular vesicles (EVs) provide a cell-free alternative with reduced immunogenicity and greater manufacturing consistency. In preclinical models, MSC-derived EVs suppress inflammation, improve GVHD scores, and prolong survival [ 165 , 166 ]. Further work is required to determine optimal dosing, administration routes, and long-term efficacy before clinical application.

Standardization of manufacturing processes has also improved reproducibility. The MSC-FFM (Frankfurt am Main) product has shown efficacy in pediatric and adult patients with steroid-refractory aGVHD, as demonstrated in multicenter studies [ 144 , 145 , 147 ]. It has also been effective in ruxolitinib-resistant cases, achieving high remission rates and extended survival [ 146 ]. These developments provide a framework for scalable and standardized MSC production.

Patient-specific factors influence therapeutic outcomes, highlighting the need for precision screening. Pretreatment lymphocyte counts and inflammatory marker levels have emerged as predictive biomarkers of MSC responsiveness [ 138 ]. Stratification of patients according to these parameters could enhance therapeutic precision and reduce heterogeneity in clinical results.

AA

Pathophysiology and MSC Dysfunction in AA

AA impairs hematopoietic stem cell (HSC) function and induces profound MSC dysfunction, destabilizing the bone marrow microenvironment. Reduced levels of platelet-derived growth factor-BB (PDGF-BB) compromise MSC proliferation and hematopoietic support. Supplementation with recombinant PDGF-BB or platelet lysates partially restores MSC activity [ 167 ].

Downregulation of VCAM1/CD106 in MSCs further disrupts HSC–MSC interactions and weakens NF-κB signaling, a pathway essential for hematopoiesis [ 168 ]. CD8 + T-cell dysfunction also contributes by reducing sensitivity to parathyroid hormone, which impairs Wnt signaling and shifts MSC differentiation toward adipogenesis rather than osteogenesis [ 169 ]. This process is reinforced by miR-146b-5p, which stabilizes PPARγ and inhibits hematopoietic support. Targeting this miRNA has therefore been proposed as a strategy to restore MSC function [ 170 ].

Epigenetic and metabolic disturbances exacerbate MSC dysfunction. Hyperactivation of DNMT1 suppresses BMP4 expression through MEG3 hypermethylation, impairing osteogenesis and hematopoietic support [ 171 ]. Overexpression of thioredoxin-interacting protein (TXNIP) promotes MSC senescence and reduces proliferation, with insulin-like growth factor 1 showing only partial efficacy in reversing these effects [ 172 ].

MSC dysfunction extends beyond hematopoietic failure to immune dysregulation. AA-derived MSCs produce excessive IL-6, IFN-γ, TNF-α, and IL-1β, which establish a pro-inflammatory microenvironment [ 173 ]. The disrupted Treg/Th17 balance, characterized by Th17 overactivation and reduced TGF-β secretion, further accelerates disease progression [ 174 ]. These findings highlight immune homeostasis and inflammatory signaling as critical therapeutic targets to restore MSC-mediated hematopoietic recovery.

Therapeutic Applications of MSCs in AA

Preclinical studies demonstrate that MSCs suppress pro-inflammatory cytokines, such as IFN-γ and TNF-α, while promoting Treg expansion and restoring the Treg/Th17 balance [ 19 , 62 ]. MSC-derived EVs deliver miRNAs, including miR-223 and miR-146a , that modulate inflammatory responses and support HSC function [ 19 , 62 ]. Their enrichment with sphingosine 1-phosphate also promotes Treg differentiation via S1PR1 signaling [ 175 ]. In contrast, EVs derived from AA patients show dysregulated cargo, including elevated miR-139-5p, which disrupts PI3K/AKT, mTOR, and MAPK signaling and enhances JAK/STAT activation, contributing to uncontrolled T-cell proliferation [ 176 , 177 ]. Targeting these dysregulated pathways may enhance the therapeutic efficacy of MSC-derived EVs.

Beyond immunoregulation, MSCs secrete angiogenic and hematopoietic factors, including VEGF, ANG-1, and TGF-β1, which directly support hematopoiesis [ 40 ]. MSCs with increased VCAM-1 expression further improve hematopoietic reconstitution in AA models [ 178 ]. Clinical studies, particularly when MSCs are combined with haploidentical HSCT [ 42 , 179 ], suggest accelerated engraftment, reduced GVHD incidence, and improved transplant outcomes [ 59 ]. MSC-derived EVs also represent a scalable, less immunogenic alternative to whole-cell therapy, with early studies showing comparable efficacy in mitigating bone marrow failure.

Despite these encouraging findings, limitations remain. The immunosuppressive properties of MSCs may dampen the GVL effect, creating a therapeutic trade-off [ 59 ]. Approaches such as combining low-dose post-transplant cyclophosphamide with UC-MSC infusion show promise in reducing GVHD while preserving immune surveillance [ 151 ]. However, several studies report that MSC infusion does not significantly improve early treatment responses or long-term survival [ 152 ].

ITP

Evidence indicates that MSC dysfunction contributes to the pathogenesis of ITP by impairing immune regulation and disrupting thrombopoiesis. BM-MSCs from patients with ITP display reduced immunomodulatory capacity, including diminished induction of CD8⁺CD28⁻ suppressor T cells and regulatory dendritic cells [ 45 , 180 ]. This dysfunction promotes immune imbalance and platelet destruction driven by autoimmunity. In addition, disruption of the CXCL12/CXCR4 axis impairs megakaryocyte migration [ 181 ], and TNFAIP3 downregulation activates NF-κB and SMAD7, leading to bone marrow dysfunction and decreased platelet production [ 182 ]. Therapeutic approaches such as ATRA and PDGF-BB treatment restore MSC function by reducing apoptosis and enhancing immunomodulatory activity [ 183 , 184 ].

Based on these mechanistic insights, MSCs are regarded as dual-action therapies in ITP, capable of correcting immune dysregulation and supporting thrombopoiesis. Preclinical models demonstrate that BM-MSC transplantation elevates platelet counts and restores immune balance through TGF-β1 and IL-10 [ 21 , 22 ]. UC-MSCs achieve sustained platelet recovery and demonstrate favorable safety in primary ITP [ 185 ]. Early-phase trials in refractory cases report encouraging response rates [ 39 ], highlighting the need for larger-scale studies. MSC-derived EVs, such as AD-MSC exosomes enriched with miR-199a-5p , provide a cell-free alternative that alleviates immune dysregulation and thrombocytopenia [ 58 ].

MDS

Evidence shows that MDS pathogenesis extends beyond intrinsic HSC defects. Alterations in the bone marrow microenvironment, particularly MSC dysfunction, play a central role in disease progression [ 186 ]. Hypoxia in the marrow induces apoptosis and cell cycle arrest in MSCs, resulting in impaired hematopoietic support [ 187 ]. Activation of HIF-1α further shifts MSCs toward a pro-inflammatory and immunosuppressive phenotype, reinforcing MSC–HSC dysregulation and promoting immune evasion [ 187 ].

Dysregulated signaling within MSCs accelerates this process. Abnormal activation of Notch and Wnt pathways disrupts MSC–HSC interactions and stimulates excessive secretion of TGF-β and IL-6. These cytokines impair hematopoiesis and establish a chronic inflammatory niche [ 188 ]. The histone variant mH2A1.1 strengthens this phenotype by activating the TLR4–NF-κB axis, amplifying immune dysregulation and hematopoietic suppression [ 189 ]. In parallel, MSC dysfunction promotes immune evasion by elevating ROS levels, reducing NK cell cytotoxicity, and expanding MDSCs [ 190 ]. Additionally, TIGIT/CD155 overactivation promotes NK cell exhaustion, further sustaining malignant clonal dominance [ 115 ]. Targeting these pathways, including Notch/Wnt and mH2A1.1-mediated inflammation, may restore immune surveillance and suppress MSC-driven progression.

MSC-derived EVs contribute to hematopoietic dysregulation by transferring pathological miRNAs to hematopoietic progenitors, inducing genomic instability and oxidative stress [ 191 ]. Notably, exosomal miR-486-5p activates TNF signaling, upregulates HOXA9, and disrupts ribosomal protein S14 function, leading to ROS accumulation and DNA damage in HSCs, which drives disease progression [ 191 ]. Targeting MSC-derived exosomal miRNAs offers a potential avenue to counteract hematopoietic dysfunction and clonal evolution in MDS.

Restoring MSC function is another therapeutic strategy. Modulation of Smad2/3 reverses suppression of hematopoietic support [ 192 ]. Luspatercept, a Smad2/3 modulator, has been shown to restore MSC-secreted SDF-1, improving HSC adhesion and mitigating ineffective hematopoiesis [ 192 ].

AML

MSC-Driven Microenvironmental Remodeling in AML

AML cells profoundly reprogram MSCs within the bone marrow niche, altering their differentiation trajectory, metabolic function, and cytokine secretome, ultimately establishing a leukemia-supportive microenvironment [ 87 , 103 ]. Representative mechanisms of AML-induced MSC remodeling are summarized in Table 4 . AML-derived EVs drive MSC differentiation away from osteogenesis and toward adipogenesis by upregulating FABP4 and suppressing alkaline phosphatase (ALP) activity, ultimately impairing normal hematopoietic support [ 122 ]. Additionally, AML-derived sEVs inhibit MSC osteogenesis via YBX1, preserving an adipogenic and chondrogenic phenotype that sustains AML proliferation [ 124 ]. Given the pivotal role of EV-mediated AML-associated MSC (AML-MSC) interactions, targeting FABP4 and YBX1 pathways may provide novel therapeutic strategies.

Beyond EV-driven mechanisms, AML-MSCs exhibit intrinsic differentiation abnormalities, further reinforcing their tumor-supportive functions. The downregulation of adipogenesis-associated transcription factors SOX9 and EGR2 enhances MSC adipogenic commitment, promoting the secretion of free fatty acids and pro-tumorigenic factors that sustain leukemic cell growth [ 198 ]. AHNAK2 gene mutations and AKR1C1 upregulation further disrupt the adipogenic balance, increasing the risk of AML relapse [ 108 , 193 ]. Targeting MSC differentiation pathways may mitigate AML niche support. Additionally, epigenetic modifications contribute to MSC dysfunction, with m6A methyltransferase METTL3 downregulation impairing differentiation potential and promoting adipogenesis [ 15 ]. Restoring METTL3 expression has been shown to partially reverse MSC functional abnormalities and weaken their tumor-supportive role, representing an epigenetic target [ 15 ].

AML-MSC interactions reinforce bone marrow fibrosis through TGF-β1-driven pro-fibrotic reprogramming, disrupting hematopoietic homeostasis and reinforcing leukemic adaptation [ 197 ]. This fibrotic remodeling fosters a pathological niche that further supports the progression of AML. Strategies aimed at blocking TGF-β1 or preventing the fibrotic transformation of MSCs may help restore bone marrow homeostasis [ 197 ].

Within the AML niche, MSCs actively contribute to chemoresistance and immune evasion. CXCL12 secretion by AML-MSCs enhances leukemic proliferation and survival through CXCR4-mediated activation of the PI3K/Akt and ERK pathways [ 200 ]. This axis also promotes cell-adhesion-mediated drug resistance (CAM-DR), limiting the efficacy of standard chemotherapy agents, such as cytarabine and anthracyclines. Additionally, elevated ATG5 expression in AML-MSCs increases CXCL12 secretion, accelerating leukemic cell cycle progression and reducing sensitivity to histone deacetylase inhibitors such as panobinostat [ 109 ]. Targeting the CXCL12-CXCR4 axis with CXCR4 antagonists, such as plerixafor (AMD3100), or disrupting autophagy-related pathways, has shown efficacy in overcoming MSC-mediated drug resistance [ 109 ].

AML-MSCs act as a major reservoir of key pro-inflammatory cytokines, including IL-6 and CXCL8 (IL-8), which orchestrate leukemic survival and chemoresistance through distinct molecular circuits. IL-8 predominantly signals through PI3K/Akt, enhancing AML proliferation and immune evasion [ 107 ], while IL-6 activates JAK2/STAT3, promoting epithelial-mesenchymal transition and resistance to chemotherapy [ 110 ]. Although AML cells also produce these cytokines, MSC-derived IL-6 and IL-8 play a central role in shaping a tumor-supportive microenvironment, reinforcing leukemic progression and therapeutic resistance [ 107 , 110 ]. Targeting these inflammatory pathways may provide novel strategies to disrupt MSC-mediated AML progression. Additionally, galectin-3 secretion by AML-MSCs further exacerbates chemoresistance via MYC and AKT activation, identifying it as a target for combination therapies [ 201 ].

At the metabolic level, AML-MSCs facilitate leukemic survival by sustaining OXPHOS and the tricarboxylic acid cycle [ 74 ]. Nestin + MSC subpopulations supply metabolic substrates that fuel AML proliferation [ 74 ]. Furthermore, AML-MSCs directly transfer mitochondria to leukemic cells, enhancing OXPHOS while mitigating oxidative stress via glutathione and associated peroxidases, thereby reinforcing chemotherapy resistance and promoting AML persistence [ 74 ]. Blocking mitochondrial transfer using monoclonal anti-CD38 antibodies, such as daratumumab, has been shown to disrupt AML metabolic adaptation and enhance chemosensitivity [ 202 ].

Beyond metabolic adaptation, MSCs establish direct cell-cell communication with AML cells via gap junctions, facilitating the exchange of signaling molecules that promote drug resistance [ 196 ]. AML-MSCs upregulate ATP-binding cassette (ABC) transporters, enhancing drug efflux and supporting the formation of a dormant, therapy-resistant side population [ 195 ]. This mechanism is particularly relevant to leukemia stem cells (LSCs), which rely on ABC transporter activity for drug resistance and long-term survival. Targeting gap junctions or inhibiting ABC transporters represents a therapeutic approach to counteract AML chemoresistance [ 195 , 196 ].

MSC-derived EVs further contribute to AML progression by delivering oncogenic miRNAs, such as miR-26a-5p , which activates Wnt/β-catenin, promoting leukemic proliferation and invasion [ 14 ]. Additionally, secreted frizzled-related protein 4 from MSC-derived exosomes facilitates Wnt/β-catenin activation, reinforcing leukemic adaptation to the microenvironment [ 87 ]. Given their crucial role in the progression of AML, targeting exosome-mediated signaling may provide therapeutic benefit.

Therapeutic Applications of MSCs in AML

MSCs are being investigated as therapeutic agents in AML because of their ability to secrete bioactive molecules and modulate the leukemic bone marrow microenvironment [ 117 ]. Recent studies have highlighted MSC-derived exosomes as key mediators of AML pathophysiology, carrying regulatory RNAs and proteins that modulate tumor growth, drug resistance, and immune evasion. Leveraging these exosomes for therapeutic intervention may help disrupt AML progression.

A primary approach involves harnessing MSC-derived exosomes enriched with miRNAs that target critical oncogenic pathways. Notably, miR-7-5p delivered by MSC-derived exosomes suppresses AML proliferation and induces apoptosis by inhibiting the PI3K/Akt/mTOR pathway [ 89 ]. Similarly, miR-23b-5p downregulates TRIM14 expression [ 91 ], reducing AML cell proliferation and enhancing apoptotic responses. Additionally, miR-139-5p inhibits the Wnt/β-catenin pathway, concurrently promoting apoptosis [ 93 ], while miR-124-5p suppresses the structural maintenance of chromosome 4 protein, amplifying apoptotic cascades [ 92 ].

Additionally, MSC-derived exosomes actively modulate immune responses, contributing to the progression of AML and therapeutic resistance. Exosomes secreted by BM-MSCs are enriched with miR-222-3p , which suppresses interferon regulatory factor 2 and downregulates inositol polyphosphate-4-phosphatase type II, collectively disrupting the PI3K/Akt axis and enhancing the apoptosis of AML cells via caspase-3 activation [ 66 , 90 ]. This dual regulation significantly impairs AML cell survival, supporting its therapeutic relevance [ 66 , 90 ].

In addition to miRNAs, MSC-derived exosomes contain long non-coding RNAs (lncRNAs), including MALAT1 , HOTAIR , and H19 , which regulate key metabolic and apoptotic pathways [ 94 ]. These lncRNAs modulate tumor suppressor genes, such as p53 and p21 , suppressing AML proliferation [ 94 ]. Furthermore, MSC-derived exosomes influence ROS homeostasis, promoting apoptosis, while downregulating anti-apoptotic factors such as BCL2 and c-Myc [ 94 ].

MSCs have also been studied in differentiation therapy, offering an alternative strategy to induce AML cell maturation and reduce tumor burden. UC-MSCs have been shown to induce AML differentiation through the secretion of neutrophil-elastase-coated exosomes, significantly reducing tumor burden [ 23 ]. Furthermore, activators of the vitamin D receptor (VDR), such as 1,25-dihydroxyvitamin D3, enhance the differentiation-inducing capability of MSCs, while minimizing hypercalcemia risk, thereby optimizing differentiation-based therapeutic strategies [ 23 ]. The combination of the non-steroidal VDR agonist SW-22 with MSC-derived exosomes has demonstrated efficacy in preclinical AML models, effectively mitigating disease progression [ 23 ].

ALL

MSC-Driven Microenvironmental Remodeling in ALL

ALL reprograms MSCs, transforming them into a leukemia-supportive phenotype that fosters leukemic survival, proliferation, and therapy resistance (Table 5 ). ALL cells actively reshape the bone marrow niche by secreting cytokines that reprogram MSCs, reinforcing leukemia-supportive interactions. In B-cell acute lymphoblastic leukemia (B-ALL), leukemic cells release CCL2, which activates STAT3 in MSCs, upregulating periostin (POSTN) expression [ 97 ]. POSTN further enhances CCL2 secretion in leukemia cells via the integrin-ILK-NF-κB axis, forming a positive feedback loop that accelerates leukemic expansion [ 97 ]. Targeting STAT3 or integrin signaling disrupts this axis, reducing the leukemia burden in preclinical models [ 97 ].

MSCs exposed to ALL cells frequently acquire a CAF-like phenotype, primarily driven by TGF-β signaling [ 120 ]. These transformed MSCs secrete SDF-1, activating CXCR4 to enhance ALL migration, invasion, and chemoresistance [ 120 , 125 ]. Additionally, CAF-derived fibronectin interacts with leukemic integrins, activating PI3K/AKT, and further promoting leukemia progression [ 125 ]. Pharmacologic blockade of the CXCR4-SDF-1 axis mitigates MSC-mediated support and enhances therapeutic responses [ 125 ]. Moreover, B-ALL cells release mitochondrial double-stranded RNA, which triggers STAT and IRF activation in MSCs, further reinforcing CAF transformation [ 203 ]. These CAF-like MSCs then transfer mitochondria to leukemia cells via tunneling nanotubes (TNTs), enhancing metabolic fitness and therapy resistance [ 203 ]. Blocking ICAM-1, a key regulator of TNT formation, effectively disrupts mitochondrial transfer and sensitizes leukemia cells to chemotherapy [ 211 ].

EVs secreted by ALL cells further modulate MSC function, reinforcing a leukemia-permissive microenvironment. T-cell acute lymphoblastic leukemia (T-ALL)-derived sEVs transfer miR-34a-5p , which suppresses the Wnt/β-catenin pathway in MSCs by targeting WNT1, impairing osteogenic differentiation, and contributing to leukemia-associated osteoporosis [ 210 ]. Restoring Wnt signaling in MSCs may offer therapeutic benefits [ 210 ]. In BCR-ABL1 + B-ALL, MSCs secrete sEVs enriched with syntenin and syndecan-1, because of PLEKHM1 deficiency [ 208 ]. These sEVs activate focal adhesion kinase and AKT signaling in LSCs, promoting leukemic cell expansion and aggressiveness [ 208 ]. Moreover, TNF-α and IL-1β from leukemia cells suppress PLEKHM1, creating a positive feedback loop that accelerates the progression of leukemia [ 208 ].

MSC-ALL adhesion via cadherin and integrin signaling enforces leukemic dormancy and minimal residual disease by upregulating drug efflux pumps (P-gp, CD34) and downregulating CD38, conferring resistance to chemotherapy and immune clearance [ 204 ]. Disrupting these adhesion-mediated mechanisms has been shown to enhance treatment efficacy and lower relapse rates [ 204 ].

Metabolic reprogramming within the MSC niche further drives the progression of ALL. In T-ALL, MSC-driven metabolic reprogramming involves ERK-mediated Drp1 phosphorylation, shifting leukemia cells from OXPHOS to glycolysis [ 212 ]. This shift minimizes mitochondrial ROS accumulation, enabling leukemia cells to evade oxidative stress and chemotherapy-induced damage [ 212 ]. Additionally, ALL cells exploit MSC-derived metabolic support by secreting glutamine, which MSCs convert glutamine into asparagine via glutamine synthetase (GS), a key process that enables ALL survival in asparagine-deprived conditions and confers resistance to L-asparaginase [ 205 ]. Blocking GS activity or disrupting glutamine transport pathways may overcome MSC-mediated drug resistance [ 205 ].

ALL cells induce MSC senescence, triggering senescence-associated secretory phenotype (SASP) enriched in IL-6, CCL2, and IL-8, which reinforces leukemia cell survival and immune evasion through chronic inflammation [ 207 ]. Importantly, MSC senescence is reversible upon ALL removal, highlighting SASP modulation or MSC rejuvenation as potential therapeutic strategies [ 207 ].

Therapeutic Applications of MSCs in ALL

Chen et al. developed MSCs engineered to secrete soluble tumor necrosis factor-related apoptosis-inducing ligand (sTRAIL), which selectively induces apoptosis of leukemic cells by inhibiting the PI3K/AKT and MEK/ERK pathways, while simultaneously activating both intrinsic and extrinsic apoptotic mechanisms [ 49 ]. In vivo studies have demonstrated that MSC-sTRAIL suppresses tumor growth and prolongs TRAIL bioavailability, reducing leukemia-associated organ damage [ 49 ].

Beyond acting as therapeutic carriers, MSCs also interact with immune-based therapies. Zanetti et al. demonstrated that BM-MSCs from B-ALL patients suppress normal T-cell proliferation, but do not impair the cytotoxic function of CD19-CAR T cells [ 206 ]. In vivo studies further confirmed that CAR-T cells effectively control B-ALL progression even in the presence of MSCs, suggesting that MSCs do not interfere with CAR-T cell efficacy [ 206 ]. However, MSCs have been implicated in modulating T-cell exhaustion and persistence, raising questions regarding their long-term influence on CAR-T function.

While MSC-based therapies hold potential, their role in the ALL microenvironment necessitates careful consideration. Mallampati et al. reported that tyrosine kinase inhibitors (TKIs) inadvertently modify MSC function, increasing the secretion of chemokines, adhesion molecules, and pro-survival factors, thereby contributing to BCR-ABL1 + B-ALL drug resistance [ 213 ].

CML

MSC-Driven Microenvironmental Remodeling in CML

CML-MSC interactions reprogram the bone marrow niche, fostering an immune-evasive and drug-resistant microenvironment that sustains LSCs. CML cells alter MSC function via exosome-mediated signaling, genetic modulation, and cytokine secretion, while MSCs reciprocally promote leukemic progression by reinforcing a pro-tumor niche.

Exosome-mediated remodeling of MSCs plays a pivotal role in this process. CML-derived exosomes upregulate CXCL12, IL-6, and DKK1 in MSCs while suppressing ROS and increasing nitric oxide production, fostering an immune-suppressive microenvironment [ 113 ]. This shift polarizes macrophages toward TAMs, further enhancing LSC survival and TKI resistance [ 113 ]. Additionally, exosomal miR-711 downregulates CD44 in MSCs, disrupting MSC-CML adhesive interactions and facilitating leukemic dissemination [ 214 ]. Targeting exosome-driven pathways may provide a novel strategy to disrupt MSC support in leukemia.

Beyond exosomal remodeling, the BCR-ABL1 fusion gene amplifies MSC dysfunction via miR-130a/b-3p upregulation through C/EBPβ activation [ 215 ]. These miRNAs downregulate Cx43, impairing MSC-CML gap junction communication and promoting immune evasion [ 215 ]. Additionally, miR-130a/b enhances CXCL10 and IFNB1 expression via PI3K/AKT activation, reinforcing MSC-mediated leukemia support [ 215 ]. Targeting miR-130a/b may restore MSC homeostasis and attenuate its pro-leukemic effects.

Cytokine-mediated signaling further contributes to this leukemia-supportive niche. MSC-derived IL-7 activates JAK1/STAT5, driving CML proliferation independent of BCR-ABL1 signaling [ 100 ]. This mechanism plays a key role in TKI resistance, positioning the IL-7/JAK1/STAT5 axis as a potential therapeutic target [ 100 ].

Therapeutic Applications of MSCs in CML

MSC-driven differentiation therapy has emerged as a promising approach to overcome LSC resistance. A combination of UC-MSCs and eltrombopag, an MPL agonist, has been shown to induce megakaryocytic differentiation of CML cells [ 216 ]. Zuo et al. demonstrated that UC-MSCs restore MPL expression, a key differentiation regulator, while eltrombopag enhances this effect via JAK/STAT and MAPK activation [ 216 ]. This strategy suppresses CML proliferation and reduces the leukemic burden, highlighting a potential differentiation-based therapy [ 216 ].

MSC integrity may serve as a biomarker for the response to TKIs. Petinati et al. found that downregulation of FGFR2 and MMP2 in BM-MSCs correlated with withdrawal syndrome and disease relapse in patients with CML [ 217 ]. Additionally, prolonged exposure to TKIs downregulates key stem cell maintenance genes ( SOX9 , PDGFRα , LIF ), impairing MSC function and sustaining LSC persistence [ 217 ]. These findings suggest that monitoring MSC integrity may help optimize TKI withdrawal strategies and minimize the risk of relapse [ 217 ].

Beyond leukemia progression, MSC dysfunction has been implicated in cancer-associated cachexia (CAC), a debilitating condition in advanced CML. Wan et al. reported that CML-derived exosomal miR-92a-3p downregulates C/EBPα in MSCs, suppressing adipogenesis and disrupting metabolic homeostasis [ 218 ]. This alteration exacerbates the progression of CAC, suggesting that targeting MSC metabolic pathways may mitigate cachexia and improve the quality of life of patients [ 218 ].

In addition to these functional insights, recent studies have reported that bone marrow-derived MSCs from newly diagnosed CML patients exhibit altered differentiation potential toward osteoblast, adipocyte, and chondrocyte lineages, alongside an enhanced ability to promote the proliferation of leukemic CD34⁺ progenitor cells [ 219 ]. These intrinsic stromal abnormalities may contribute to leukemic niche formation and highlight the need for targeted stromal correction strategies in CML.

MM

While MM is primarily driven by intrinsic genetic aberrations, the bone marrow microenvironment plays a crucial role in disease initiation, progression, and therapeutic resistance. Among its various stromal components, MSCs have emerged as key regulators of the pathophysiology of MM, fostering tumor cell survival, immune evasion, and drug resistance [ 220 – 222 ] (Table 6 ).

MM reprograms MSCs into a tumor-supportive niche, promoting disease progression, immune evasion, and therapeutic resistance. Through diverse mechanisms, MM cells induce MSC dysfunction, reinforcing a permissive microenvironment that supports MM survival and relapse. One key mechanism involves the downregulation of the RNA-processing enzyme Dicer1 in MSCs, leading to increased secretion of IL-6 and CXCL12, which in turn, promotes MM proliferation and chemoresistance [ 98 ]. The restoration of Dicer1 expression has been shown to reverse these effects, highlighting a potential strategy to counteract MM-induced MSC dysfunction [ 98 ]. Additionally, MM-derived exosomes transfer oncogenic miRNAs, such as miR-21 and miR-146a , driving MSC transformation into CAF-like cells [ 121 ]. These CAF-like MSCs secrete elevated levels of IL-6, fibroblast activation protein, and α-SMA, further sustaining MM growth and therapy resistance [ 121 ]. Targeting miR-21 and miR-146a has been shown to impair CAF formation and mitigate MSC-driven tumor support [ 121 ].

Beyond sustaining MM survival, MSCs further disrupt bone homeostasis by altering their differentiation potential. MM-derived exosomal miR-129-5p suppresses key osteogenic transcription factors such as Sp1 and ALPL [ 123 ], while the activation of PKCβ1 via α4 integrin-VCAM1 interactions stabilizes PPARγ2 [ 235 ], shifting MSC differentiation toward adipogenesis. Additionally, hypermethylation of Homeobox genes further impairs MSC osteogenic potential [ 230 ]. Strategies targeting miR-129-5p , the α4 integrin-VCAM1 axis, or DNA hypermethylation may help restore MSC-mediated bone homeostasis.

Through diverse molecular pathways, MSCs reinforce MM stemness and therapy resistance, primarily through NF-κB and CXCL13-CXCR5-BTK signaling. Upregulation of autophagy-related genes, including LC3 and Beclin-1, enhances MM survival by suppressing apoptosis and increasing resistance to therapy [ 240 ]. Pro-inflammatory cytokines, such as TNF-α and IL-1β, further sustain NF-κB activation, amplifying MM progression and reducing treatment efficacy [ 241 ]. NF-κB inhibition, especially with autophagy inhibitors, has shown potential in reversing MSC-mediated MM resistance [ 221 , 240 , 241 ]. Meanwhile, the CXCL13-CXCR5-BTK axis represents another key pathway through which MSCs drive MM progression [ 236 ]. CXCL13 secreted by MSCs binds to CXCR5 on MM cells, activating both BTK and NF-κB, which cooperatively sustain anti-apoptotic signaling and therapy resistance [ 236 ]. Notably, increased BTK activity enhances MM stemness and contributes to disease relapse, highlighting the CXCL13-CXCR5-BTK axis as a promising therapeutic target [ 242 ].

MSCs also promote MM progression through enhanced adhesion and ECM remodeling. The IRE1α-FilaminA axis increases MSC migration and direct MM cell contact, fostering tumor growth and therapy resistance [ 224 ]. Simultaneously, the Table 1-TIMP-1 axis remodels the ECM, altering MMP activity and increasing MM invasiveness [ 111 ]. These ECM-driven changes further contribute to the immune evasion of MM cells. Targeting ECM remodeling and adhesion signaling may thus improve treatment efficacy by limiting both MM dissemination and immune suppression [ 111 , 224 ].

Additionally, MSCs contribute to immune evasion by suppressing both innate and adaptive immune responses. Elevated CD155 expression on MSCs interacts with TIGIT receptors on NK cells, impairing their cytotoxic function by reducing perforin and IFN-γ secretion [ 229 ]. Furthermore, MSCs upregulate PD-L1, leading to the suppression of CD8 + T cell activity and facilitating MM immune escape [ 231 ]. MM patient-derived MSCs further exacerbate immune evasion by downregulating antigen presentation genes, such as HLA-DRA, thus reducing immune recognition [ 239 ]. In addition to dampening antitumor immunity, MSCs also impair CAR-T cell toxicity [ 233 ]. The upregulation of anti-apoptotic proteins, including Survivin and Mcl-1, inhibits CAR-T cell efficacy, contributing to therapy resistance [ 233 ]. Moreover, histone citrullination via PADI2 enhances MSC-induced IL-6 secretion, reinforcing MM cell survival and therapy resistance [ 101 ]. Targeting MSC-driven immune suppression through PD-1/PD-L1 and TIGIT/CD155 blockade, alongside strategies to overcome CAR-T cell resistance, may enhance the efficacy of immunotherapy in MM.

MSC-derived EVs serve as critical mediators of MM progression by delivering bioactive molecules that promote apoptosis resistance, stemness maintenance, and therapy resistance [ 88 ]. Exosomal miR-483-5p downregulates TIMP2, inhibiting apoptosis and promoting MM cell survival [ 228 ]. Meanwhile, miR-155 activates the Hedgehog pathway, reinforcing MM stemness and contributing to disease relapse [ 118 ]. Additionally, miR-182 , transcriptionally regulated by HIF-1α, enhances MM proliferation and confers resistance to proteasome inhibitors [ 226 ]. Beyond miRNA-mediated modulation, MSC-derived EVs also sustain MAPK signaling and upregulate translation initiation factors such as eIF4E, further supporting MM survival and migration [ 243 ]. Targeting EV-associated mechanisms may provide a novel strategy for overcoming MSC-driven MM support.

Beyond their tumor-supportive role, MSC-derived EVs also exhibit potential anti-myeloma properties [ 223 ]. BM-MSC-derived EVs have been shown to induce the apoptosis of MM cells by upregulating BAX and downregulating BCL-2 and CCND1, largely via the activation of DNA damage response pathways [ 223 ]. Genetic engineering or biochemical modification of MSC-derived EVs may enhance their pro-apoptotic potential, while mitigating their tumor-promoting effects, representing a novel therapeutic avenue for MM. However, further preclinical and clinical validations are required to determine the efficacy and safety of MSC-based EV therapy in patients with MM [ 223 ].

Current Challenges in MSC-Based Therapy

Variability in Therapeutic Efficacy

The clinical efficacy of MSC-based therapies remains highly variable, posing a major barrier to their widespread adoption. This heterogeneity stems from multiple factors, including differences in donor sources, culture conditions, expansion protocols, and host microenvironments, all of which affect MSC functional properties [ 244 ]. These inconsistencies contribute to unpredictable therapeutic outcomes across different diseases and patient populations. The absence of standardized potency assays further complicates prediction of MSC functionality, underscoring the need for robust preclinical models and optimized manufacturing protocols [ 245 ].

Safety Concerns and Potential Risks

MSC therapy must balance therapeutic immunosuppression with potential immunological risks. While MSCs effectively mitigate inflammatory damage, they may also impair the host immune defense, increasing susceptibility to infections, particularly in immunocompromised individuals [ 143 ]. In GVHD, excessive immunosuppression may compromise the GVL effect and increase relapse risk. In hematologic malignancies, MSC-induced immune evasion may allow minimal residual disease to persist [ 117 ]. Although direct evidence linking MSCs to tumorigenesis is lacking, their capacity to remodel the tumor microenvironment raises long-term safety concerns [ 18 , 95 , 96 ]. Long-term follow-up is therefore essential to evaluate potential pro-tumorigenic effects. Additionally, MSC infusion has been associated with dose-dependent coagulation abnormalities, with high doses linked to thrombosis and microvascular complications [ 246 ]. Defining an optimal therapeutic window remains a major challenge.

Standardization and Clinical Translation

Clinical translation of MSCs remains hindered by inconsistencies in cell sourcing, expansion methodologies, and administration protocols [ 160 ]. Even within the same disease, variations in MSC preparation—ranging from donor selection to culture conditions—can drastically alter outcomes [ 245 ]. Rigorous quality control measures are essential to improve reproducibility. Large-scale manufacturing poses additional challenges, as batch-to-batch variability in potency complicates regulatory approval and therapeutic stability [ 247 ]. Refining MSC isolation and expansion techniques, together with advanced characterization assays, will be necessary to enhance predictability and facilitate clinical adoption.

Future Strategies for Enhancing MSC Therapy

Enhancing the Functional Properties of MSCs

Preconditioning strategies, including hypoxic exposure and inflammatory priming (e.g., IFN-γ licensing), enhance the immunosuppressive capacity of MSCs by promoting Treg induction, inhibiting effector T-cell proliferation, and increasing resistance to oxidative stress [ 163 , 164 ]. In parallel, metabolic reprogramming—particularly a shift toward glycolysis-dominant metabolism—further enhances MSC adaptation to inflammatory microenvironments [ 24 ], reinforcing their therapeutic efficacy in disorders such as GVHD. In addition to metabolic modulation, three-dimensional culture systems more closely replicate the native bone marrow niche, significantly enhancing MSC paracrine activity, prolonging cell survival, and optimizing hematopoietic niche interactions [ 248 ]. These advancements have demonstrated superior therapeutic potential in hematologic disorders such as ITP and bone marrow failure syndromes [ 248 ]. Beyond culture optimization, intrinsic MSC heterogeneity also influences therapeutic outcomes. UC-MSCs, BM-MSCs, and AD-MSCs exhibit distinct immunomodulatory capacities, hematopoietic support potential, and homing efficiency, underscoring the need for disease-specific MSC selection strategies [ 244 ].

Genetic Engineering of MSCs

Enhancing MSC functionality through gene modification has shown promising results in preclinical models. Overexpression of Akt1 strengthens MSC resistance to apoptosis, improves survival in inflammatory environments, and enhances homing to GVHD-affected tissues, reinforcing immune tolerance and reducing alloreactivity [ 162 ]. Additionally, MSCs engineered to express TRAIL or IFN-β effectively induce apoptosis in leukemia and lymphoma cells, improving survival outcomes [ 49 , 249 , 250 ].

In addition to improving MSC functionality, genetic modifications allow MSCs to serve as therapeutic carriers. Zhang et al. designed IL-6/CD20 bispecific antibody-expressing UC-MSCs, which simultaneously target diffuse large B-cell lymphoma while modulating IL-6 signaling to improve the tumor microenvironment and enhance the efficacy of immunotherapy [ 251 ]. Wang et al. demonstrated that MSCs encapsulate reovirus lysate virus, providing immune shielding that enhances AML cell cytotoxicity and induces immune activation via CXCL10, amplifying the anti-tumor response [ 252 ]. Additionally, Bu et al. developed an AAV-engineered UC-MSC platform that enables sustained secretion of coagulation factor IX in hemophilia B, circumventing the immune responses and hepatotoxicity associated with direct viral administration, providing a safer gene therapy approach [ 48 ].

Despite these advances, several challenges remain unresolved, including long-term safety, off-target effects, and immune risks associated with genetically modified MSCs, all of which require further investigation. The advent of CRISPR/Cas9-mediated gene editing offers unprecedented precision in MSC engineering, enabling selective enhancement of therapeutic functions, while minimizing unintended consequences. Moving forward, integrating MSC genetic modifications with combination therapies, such as HSCT, CAR-T cell therapy, and immune-based interventions, will further refine their clinical applications and expand their therapeutic potential in hematologic diseases.

Combination Therapy with MSCs

In the context of HSCT, MSC-based therapies have been extensively studied for GVHD prevention, hematopoietic recovery, and graft facilitation [ 139 ]. While their immunosuppressive properties help control GVHD, they may also attenuate GVL effects, reducing MRD clearance and increasing the risk of relapse. Optimizing MSC infusion protocols, including the dose, timing, and donor selection, remains key to balancing GVHD mitigation with anti-leukemia immunity.

MSC-mediated immunomodulation has generated interest as a potential adjunct in CAR-T cell therapy. While preclinical studies suggest that MSCs can modulate inflammatory responses, their impact on mitigating CRS and ICANS remains speculative and requires further investigation. Additionally, MSCs support hematopoietic recovery [ 41 , 155 ], which may be beneficial in cases of CAR-T-cell-induced myelosuppression. However, the immunosuppressive effects of MSCs may also interfere with CAR-T cell expansion and persistence, potentially exacerbating T-cell exhaustion and reducing treatment durability [ 65 ]. Moreover, the interactions of MSCs with the tumor microenvironment may, in some cases, promote immune evasion and weaken CAR-T-cell-mediated anti-tumor activity. Therefore, precise timing, dosing, and patient selection strategies will be critical.

In chemotherapy, MSCs contribute to hematopoietic support and microenvironmental remodeling [ 253 ]. By secreting hematopoietic cytokines, modulating ECM dynamics, and reducing inflammation, MSCs alleviate chemotherapy-induced myelosuppression and promote bone marrow recovery, particularly in patients receiving high-dose or myelotoxic regimens [ 27 ].

Acellular Therapy: MSC-Derived EVs

MSC-derived EVs have emerged as a promising acellular alternative to MSC-based therapies. In hematologic disorders, MSC-derived EVs have shown potential in GVHD management, hematopoietic reconstitution, and malignancy treatment. In GVHD, EVs regulate donor T-cell activity, suppress pro-inflammatory cytokines, and expand Tregs, effectively controlling inflammation while minimizing excessive immunosuppression [ 166 ]. Additionally, MSC-derived EVs enhance hematopoietic recovery by promoting HSC proliferation, mitigating oxidative stress, and modulating the bone marrow microenvironment [ 254 ]. In hematologic malignancies, EVs function as natural carriers of bioactive molecules, including miRNAs and proteins, facilitating microenvironment remodeling and enhancing antitumor immune responses [ 90 , 194 ].

Despite these advantages, several challenges hinder the clinical translation of MSC-derived EVs. Unlike MSCs, which directly engage in cell-cell interactions and ECM remodeling, EVs rely solely on bioactive cargo delivery, raising concerns regarding whether they can fully replicate MSC-mediated immune regulation and tissue support. Furthermore, their pharmacokinetic properties, including biodistribution, stability, and in vivo half-life, remain incompletely characterized, necessitating further investigation to optimize their therapeutic efficacy. Standardization is another major hurdle, as variations in MSC sources, isolation techniques, and purification methods result in batch-to-batch inconsistencies.

Standardization and Clinical Translation of MSC Therapy

The clinical application of mesenchymal stem cell (MSC) therapy is often hindered by variations in culture conditions, expansion protocols, and quality control measures. These inconsistencies challenge both reproducibility and regulatory approval [ 160 ]. To address these issues, the development of standardized, Good Manufacturing Practice (GMP)-compliant production systems is crucial for ensuring the consistency, safety, and scalability of MSC-based therapies. Recent advancements in GMP-compliant MSC platforms, such as MSC-FFM, have made significant progress by introducing strict controls over culture conditions, batch-to-batch quality, and storage protocols [ 24 , 144 – 146 ]. These innovations reduce variability, improving the reproducibility of MSC products and facilitating their clinical integration.

However, MSC therapy remains complex due to patient-specific factors, including variations in immune status, genetic background, and disease microenvironment, all of which influence therapeutic outcomes. To optimize treatment precision, a biomarker-driven approach for patient stratification is essential [ 141 ]. Predictive biomarkers such as TWIST1, associated with MSC angiogenesis, and IDO, involved in immune suppression, can help tailor therapy to individual patients [ 255 ]. Additionally, metabolomics-based profiling of MSC donors enables the early identification of high-potency donors, ensuring the selection of the most effective cells for clinical applications [ 256 ]. Integrating these personalized strategies with standardized GMP-compliant production systems helps maintain consistency across MSC batches while addressing specific patient needs.

The selection of an appropriate tissue source is a critical step in standardizing MSC therapy. Different sources—such as bone marrow, adipose tissue, and umbilical cord—exhibit significant variability in proliferation rates, immunomodulatory potential, and differentiation capacity [ 257 ]. For instance, UC-MSCs are particularly advantageous in clinical applications that require large cell numbers, such as HSCT, due to their superior proliferation rates and lower senescence markers [ 17 , 23 – 25 ]. In contrast, AD-MSCs are more suited for treating immune-related disorders like GVHD due to their stronger immunosuppressive properties [ 26 , 27 ]. A tailored approach that aligns tissue selection with disease-specific needs can reduce variability and improve therapeutic outcomes.

To reduce the immunogenicity of MSC therapies, several genetic engineering strategies are under investigation. One promising approach involves the CRISPR/Cas9-mediated knockout of HLA class I and II molecules, specifically the β2-microglobulin (B2M) gene, which is essential for stable HLA expression [ 258 ]. Introducing non-classical HLA molecules, such as HLA-G, may further enhance immune evasion by interacting with NK cell inhibitory receptors [ 258 ]. These immune-evasion strategies enable the creation of off-the-shelf MSC products, which can be used across diverse patient populations without the need for individual immune profiling.

hPSC-derived MSCs present a promising solution to donor variability and tissue availability. Unlike primary MSCs, which vary based on donor age, genetic background, and tissue source, hPSC-derived MSCs offer consistency and homogeneity due to their derivation from a single clone [ 259 ]. This consistency supports large-scale clinical applications and ensures reproducibility across production batches. However, concerns regarding tumorigenicity from residual undifferentiated pluripotent cells remain a challenge [ 260 , 261 ]. To address this, suicide genes such as iCasp9 can be introduced to eliminate residual pluripotent cells before MSC administration [ 260 ]. This approach, combined with safety engineering and GMP compliance, positions hPSC-derived MSCs as a viable platform for large-scale clinical translation.

Establishing a two-tiered cell banking system is essential for ensuring the reproducibility and traceability of MSC products. The Master Cell Bank (MCB), derived from a well-characterized donor or hPSC line, serves as the foundation for subsequent MSC production. The MCB undergoes rigorous quality control testing to confirm its identity, purity, safety, and potency. The Working Cell Bank (WCB), derived from the MCB, is used for clinical applications, ensuring consistency between production batches. Adhering to GMP standards guarantees that every MSC batch meets regulatory requirements for clinical use.

Going forward, refining MSC infusion protocols and conducting large-scale, multicenter clinical trials are critical to establishing evidence-based guidelines. A summary of ongoing clinical trials evaluating MSC-based therapies in hematologic disorders is provided in Table 7 .

Conclusions

MSCs have demonstrated significant therapeutic potential in hematologic diseases because of their immunomodulatory, hematopoietic support, and regenerative properties. Their application in GVHD, ITP, and hematologic malignancies, particularly in combination with HSCT and CAR-T cell therapy, has expanded the landscape of cell-based treatments.

Despite promising results, challenges such as therapeutic heterogeneity, safety concerns, and the lack of standardized protocols limit the widespread clinical adoption of MSC therapy. Advances in metabolic reprogramming, gene modifications, and optimized culture conditions have improved MSC functionality, while MSC-derived EVs offer a cell-free alternative with enhanced stability and scalability. Furthermore, standardization of MSC manufacturing and personalized therapeutic strategies based on patient-specific biomarkers are critical for improving treatment consistency and efficacy.

Future research should focus on large-scale, multicenter clinical trials to validate long-term safety and efficacy, while emerging technologies in gene engineering and synthetic biology may further refine MSC-based approaches. With continued optimization, MSC therapies hold the potential to bridge critical gaps in hematologic disease treatment, offering more effective and personalized therapeutic strategies.

Abbreviations

Multiple myeloma

Graft-versus-host disease

Aplastic anemia

Hematopoietic stem cell transplantation

Acute myeloid leukemia

Chimeric antigen receptor T-cell

Mesenchymal stromal cells

Extracellular vesicles

Bone-marrow-derived mesenchymal stromal cells

Umbilical-cord-derived mesenchymal stromal cells

Immune thrombocytopenia

Myeloid-derived suppressor cells

Regulatory T cells

Adipose-tissue-derived mesenchymal stromal cells

Cytokine release syndrome

Gingiva-derived mesenchymal stromal cells

Indoleamine 2,3-dioxygenase

Natural killer

Dendritic cell

Oxidative phosphorylation

Hematopoietic stem cell

Stem cell factor

Hepatocyte growth factor

Angiopoietin-1

Vascular endothelial growth factor

Hematopoietic stem and progenitor cells

Myelodysplastic syndromes

Extracellular matrix

Chronic GVHD

Hypoxia-inducible factor 1-alpha

Reactive oxygen species

Tumor necrosis factor-related apoptosis-inducing ligand

Tumor-associated macrophages

Cancer-associated fibroblast

Graft-versus-leukemia

Glutathione

Acute GVHD

Platelet-derived growth factor-BB

Ribosomal protein S14

Alkaline phosphatase

AML-associated MSC

Cell-adhesion-mediated drug resistance

ATP-binding cassette

Leukemia stem cells

Long non-coding RNAs

Vitamin D receptor

B-cell acute lymphoblastic leukemia

Periostin

T-cell acute lymphoblastic leukemia

Glutamine synthetase

Secretory phenotype

Soluble tumor necrosis factor-related apoptosis-inducing ligand

Tyrosine kinase inhibitors

Cancer-associated cachexia

Minimal residual disease

Author Contributions

XMZ and XM conceptualized, designed, and drafted the initial version of the manuscript. JYW conducted the literature research and prepared the figures. YX and XJZ provided supervision and critical intellectual input. All authors contributed to the manuscript and approved the final version.

Funding

This work was supported by the National Natural Science Foundation of China (No. 81873444, No. 82070213, and No.82370196).

Data Availability

No datasets were generated or analysed during the current study.

Code Availability

Not applicable.

Declarations

Ethics approval

Not applicable.

Consent for publication

Not applicable.

Consent to participate

Not applicable.

Clinical trial number

Not applicable.

Competing interests

The authors declare no competing interests.

Footnotes

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Xumeng Zhao and Xi Ming These authors have contributed equally to this work.

Contributor Information

Xiaojian Zhu, Email: zhuxiaojian@hust.edu.cn.

Yi Xiao, Email: yixiao@tjh.tjmu.edu.cn.

References

1. Ebrahim, H., Fisha, T., Debash, H., & Bisetegn, H. (2022). Patterns of bone marrow confirmed malignant and non-malignant hematological disorders in patients with abnormal hematological parameters in Northeast Ethiopia. Journal of Blood Medicine, 13 , 51–60.

2. Alaggio, R., Amador, C., Anagnostopoulos, I., Attygalle, A. D., Araujo, I. B., de O, Berti, E., et al. (2022). The 5th edition of the world health organization classification of haematolymphoid tumours: lymphoid neoplasms. Leukemia , 36 (7), 1720–1748.

3. Khoury, J. D., Solary, E., Abla, O., Akkari, Y., Alaggio, R., Apperley, J. F., et al. (2022). The 5th edition of the world health organization classification of haematolymphoid tumours: Myeloid and histiocytic/dendritic neoplasms. Leukemia, 36 (7), 1703–1719.

4. de Leeuw, D. C., Ossenkoppele, G. J., & Janssen, J. J. W. M. (2022). Older patients with acute myeloid leukemia deserve individualized treatment. Current Oncology Reports, 24 (11), 1387–1400.

5. Bhansali, R. S., Pratz, K. W., & Lai, C. (2023). Recent advances in targeted therapies in acute myeloid leukemia. Journal of Hematology & Oncology , 16 (1), 29.

6. Roloff, G. W., Odenike, O., Bajel, A., Wei, A. H., Foley, N., & Uy, G. L. (2022). Contemporary approach to acute myeloid leukemia therapy in 2022. American Society of Clinical Oncology Educational Book American Society of Clinical Oncology Annual Meeting, 42 , 1–16.

7. Rafae, A., van Rhee, F., & Al Hadidi, S. (2024). Perspectives on the treatment of multiple myeloma. The Oncologist, 29 (3), 200–212.

8. Li, J., Xia, Y., Fan, X., Wu, X., Yang, F., Hu, S., et al. (2021). Extracellular vesicles derived from miR-199a-5p-modified adipose-derived mesenchymal stem cells alleviate immune thrombocytopenia by inhibiting T helper 17 differentiation. Laboratory Investigation, 101 (3), 318–327.

9. Shah, U. A., & Mailankody, S. (2020). Emerging immunotherapies in multiple myeloma. BMJ Clin res ed, 370, m3176. Sept 21;

10. Uccelli, A., Moretta, L., & Pistoia, V. (2008). Mesenchymal stem cells in health and disease. Nature Reviews Immunology, 8 (9), 726–736.

11. Chen, X., Wang, C., Yin, J., Xu, J., Wei, J., & Zhang, Y. (2015). Efficacy of mesenchymal stem cell therapy for steroid-refractory acute graft-versus-host disease following allogeneic hematopoietic stem cell transplantation: A systematic review and meta-analysis. PLoS One, 10 (8), Article e0136991.

12. Friedenstein, A. J., Piatetzky-Shapiro, I. I., & Petrakova, K. V. (1966). Osteogenesis in transplants of bone marrow cells. Journal of Embryology and Experimental Morphology, 16 (3), 381–390.

13. Dominici, M., Le Blanc, K., Mueller, I., Slaper-Cortenbach, I., Marini, F. C., Krause, D. S., et al. (2006). Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy, 8 (4), 315–317.

14. Ji, D., He, Y., Lu, W., Rong, Y., Li, F., Huang, X., et al. (2021). Small-sized extracellular vesicles (EVs) derived from acute myeloid leukemia bone marrow mesenchymal stem cells transfer miR-26a-5p to promote acute myeloid leukemia cell proliferation, migration, and invasion. Human Cell, 34 (3), 965–976.

15. Liao, X., Cai, D., Liu, J., Hu, H., You, R., Pan, Z., et al. (2023). Deletion of Mettl3 in mesenchymal stem cells promotes acute myeloid leukemia resistance to chemotherapy. Cell Death and Disease, 14 (12), Article 796.

16. Zoehler, B., Fracaro, L., Senegaglia, A. C., & Bicalho, M. D. G. (2020). Infusion of mesenchymal stem cells to treat graft versus host disease: The role of HLA-G and the impact of its polymorphisms. Stem Cell Reviews and Reports, 16 (3), 459–471.

17. Wang, X., Yang, Y., Wang, N., Wu, X., Xu, J., Zhou, Y., et al. (2021). Mesenchymal stem cell carriers enhance antitumor efficacy induced by oncolytic reovirus in acute myeloid leukemia. International Immunopharmacology, 94 , Article 107437.

18. Miari, K. E., & Williams, M. T. S. (2024). Stromal bone marrow fibroblasts and mesenchymal stem cells support acute myeloid leukaemia cells and promote therapy resistance. British Journal of Pharmacology, 181 (2), 216–237.

19. Shi, Q. Z., Yu, H. M., Chen, H. M., Liu, M., & Cheng, X. (2021). Exosomes derived from mesenchymal stem cells regulate treg/Th17 balance in aplastic anemia by transferring miR-23a-3p. Clinical and Experimental Medicine, 21 (3), 429–437.

20. Kim, N., Min, G. J., Im, K. I., Nam, Y. S., Song, Y., Lee, J. S. (2024). Repeated infusions of bone-marrow-derived mesenchymal stem cells over 8 weeks for steroid-refractory chronic graft-versus-host disease: a prospective, phase I/II clinical study. Int J Mol Sci, 25(12):6731. June 19

21. Tao, Y., Song, D., Zhang, F., Ren, S., Zhang, H., & Sun, L. (2017). Transplantation of bone-marrow-derived mesenchymal stem cells into a murine model of immune thrombocytopenia. Blood Coagulation & Fibrinolysis, 28 (8), 596–601.

22. Zhang, P., Zhang, G., Liu, X., Liu, H., Yang, P., & Ma, L. (2019). Mesenchymal stem cells improve platelet counts in mice with immune thrombocytopenia. Journal of Cellular Biochemistry, 120 (7), 11274–11283.

23. Sun, L., Yang, N., Chen, B., Bei, Y., Kang, Z., Zhang, C., et al. (2023). A novel mesenchymal stem cell-based regimen for acute myeloid leukemia differentiation therapy. Acta Pharmaceutica Sinica B, 13 (7), 3027–3042.

24. Mendt, M., Daher, M., Basar, R., Shanley, M., Kumar, B., Wei Inng, F. L., et al. (2021). Metabolic reprogramming of GMP grade cord tissue derived mesenchymal stem cells enhances their suppressive potential in GVHD. Frontiers in Immunology, 12 , Article 631353.

25. Zhao, L., Chen, S., Yang, P., Cao, H., & Li, L. (2019). The role of mesenchymal stem cells in hematopoietic stem cell transplantation: prevention and treatment of graft-versus-host disease. Stem Cell Res Ther, 10(1), 182.

26. Nishi, Y., Murakami, A., Murayama, Y., Tsukahara, N., Okamoto, S., Nakachi, S., et al. (2019). Adipose tissue-derived mesenchymal stem cells ameliorate bone marrow aplasia related with graft-versus-host disease in experimental murine models. Transplant Immunology, 55 , Article 101205.

27. Koç, O. N., Gerson, S. L., Cooper, B. W., Dyhouse, S. M., Haynesworth, S. E., Caplan, A. I., et al. (2000). Rapid hematopoietic recovery after coinfusion of autologous-blood stem cells and culture-expanded marrow mesenchymal stem cells in advanced breast cancer patients receiving high-dose chemotherapy. J Clin Oncol: Off J Am Soc Clin Oncol , 18 (2), 307–316.

28. Dias, I. X., Cordeiro, A., Guimarães, J. A. M., & Silva, K. R. (2023). Potential and limitations of induced pluripotent stem cells-derived mesenchymal stem cells in musculoskeletal disorders treatment. Biomolecules, 13(9), 1342.

29. Abdal Dayem, A., Lee, S. B., Kim, K., Lim, K. M., Jeon, T. I., Seok, J., et al. (2019). Production of mesenchymal stem cells through stem cell reprogramming. International Journal of Molecular Sciences, 20 (8), Article 1922.

30. Thanaskody, K., Jusop, A. S., Tye, G. J., Wan Kamarul Zaman, W. S., Dass, S. A., & Nordin, F. (2022). MSCs vs. iPSCs: Potential in therapeutic applications. Frontiers in Cell and Developmental Biology, 10 , Article 1005926.

31. West, M. D., Nasonkin, I., Larocca, D., Chapman, K. B., Binette, F., & Sternberg, H. (2016). Adult versus pluripotent stem cell-derived mesenchymal stem cells: The need for more precise nomenclature. Current Stem Cell Reports, 2 (3), 299–303.

32. Ma, Y., Wang, Z., Zhang, A., Xu, F., Zhao, N., Xue, J., et al. (2018). Human placenta-derived mesenchymal stem cells ameliorate GVHD by modulating Th17/Tr1 balance via expression of PD-L2. Life Sciences, 214 , 98–105.

33. Tago, Y., Kobayashi, C., Ogura, M., Wada, J., Yamaguchi, S., Yamaguchi, T., et al. (2021). Human amnion-derived mesenchymal stem cells attenuate xenogeneic graft-versus-host disease by preventing T cell activation and proliferation. Scientific Reports, 11 (1), Article 2406.

34. Yamahara, K., Hamada, A., Soma, T., Okamoto, R., Okada, M., Yoshihara, S. (2019). Safety and efficacy of amnion-derived mesenchymal stem cells (AM01) in patients with steroid-refractory acute graft-versus-host disease after allogeneic haematopoietic stem cell transplantation: a study protocol for a phase I/II japanese trial. BMJ open 9(7), e026403.

35. Huang, F., Chen, M., Chen, W., Gu, J., Yuan, J., Xue, Y., et al. (2017). Human gingiva-derived mesenchymal stem cells inhibit xeno-graft-versus-host disease via CD39-CD73-adenosine and IDO signals. Frontiers in Immunology, 8 , Article 68.

36. Ni, X., Xia, Y., Zhou, S., Peng, H., Wu, X., Lu, H., et al. (2019). Reduction in murine acute GVHD severity by human gingival tissue-derived mesenchymal stem cells via the CD39 pathways. Cell Death and Disease, 10 (1), Article 13.

37. Horwitz, E. M., Le Blanc, K., Dominici, M., Mueller, I., Slaper-Cortenbach, I., Marini, F. C., et al. (2005). Clarification of the nomenclature for MSC: The International Society for Cellular Therapy position statement. Cytotherapy, 7 (5), 393–395.

38. Atmar, K., Tulling, A. J., Lankester, A. C., Bartels, M., Smiers, F. J., van der Burg, M., et al. (2022). Functional and immune modulatory characteristics of bone marrow mesenchymal stromal cells in patients with aplastic anemia: A systematic review. Frontiers in Immunology, 13 , Article 859668.

39. Chen, Y., Xu, Y., Chi, Y., Sun, T., Gao, Y., Dou, X., et al. (2024). Efficacy and safety of human umbilical cord-derived mesenchymal stem cells in the treatment of refractory immune thrombocytopenia: A prospective, single arm, phase I trial. Signal Transduction and Targeted Therapy, 9 (1), Article 102.

40. He, C., Yang, C., Zeng, Q., Liu, Z., Wang, F., Chen, Q., et al. (2023). Umbilical cord-derived mesenchymal stem cells cultured in the MCL medium for aplastic anemia therapy. Stem Cell Research & Therapy , 14 (1), 224.

41. Liu, Z., Wu, X., Wang, S., Xia, L., Xiao, H., Li, Y., et al. (2020). Co-transplantation of mesenchymal stem cells makes haploidentical HSCT a potential comparable therapy with matched sibling donor HSCT for patients with severe aplastic anemia. Therapeutic Advances in Hematology, 11 , Article 2040620720965411.

42. Sheng, X. F., Li, H., Hong, L. L., & Zhuang, H. (2022). Combination of haploidentical hematopoietic stem cell transplantation with umbilical cord-derived mesenchymal stem cells in patients with severe aplastic anemia: a retrospective controlled study. Turk J Haematol: Off J Turk Soc Haematol , 39(2), 117–29.

43. Xu, L., Liu, Z., Wu, Y., Yang, X., Cao, Y., Li, X., et al. (2018). Clinical evaluation of haploidentical hematopoietic combined with human umbilical cord-derived mesenchymal stem cells in severe aplastic anemia. European Journal of Medical Research, 23 (1), Article 12.

44. Yang, D., Hou, X., Qian, K., Li, Y., Hu, L., Li, L., et al. (2023). Efficacy and safety of human umbilical cord-derived mesenchymal stem cells (hUC-MSC PLEB001) for the treatment of grade II-IV steroid-refractory acute graft-versus-host disease: A study protocol for a multicenter, randomized, double-blind, placebo-controlled, phase II trial. Trials, 24 (1), Article 306.

45. Li, H., Guan, Y., Sun, B., Dou, X., Liu, X., Xue, F., et al. (2020). Role of bone marrow-derived mesenchymal stem cell defects in CD8 + CD28- suppressor T-lymphocyte induction in patients with immune thrombocytopenia and associated mechanisms. British Journal of Haematology, 191 (5), 852–862.

46. Wang, R., Wang, X., Yang, S., Xiao, Y., Jia, Y., Zhong, J., et al. (2021). Umbilical cord-derived mesenchymal stem cells promote myeloid-derived suppressor cell enrichment by secreting CXCL1 to prevent graft-versus-host disease after hematopoietic stem cell transplantation. Cytotherapy, 23 (11), 996–1006.

47. Mendiratta, M., Mendiratta, M., Ganguly, S., Rai, S., Gupta, R., Kumar, L., et al. (2024). Concurrent hypoxia and apoptosis imparts immune programming potential in mesenchymal stem cells: Lesson from acute graft-versus-host-disease model. Stem Cell Research & Therapy , 15 (1), 381.

48. Bu, Z., Lou, J., Xu, W., Zhang, L., & Tang, Y. (2024). Human umbilical cord mesenchymal stem cell-based gene therapy for hemophilia B using scAAV-DJ/8-LP1-hFIXco transduction. Stem Cell Res Ther, 15(1), 210.

49. Chen, F., Zhong, X., Dai, Q., Li, K., Zhang, W., Wang, J., et al. (2022). Human umbilical cord MSC delivered-soluble TRAIL inhibits the proliferation and promotes apoptosis of B-ALL cell in vitro and in vivo. Pharmaceuticals, 15 (11), Article 1391.

50. Hao, X., Zhu, H., Qin, C., Li, L., Lin, Z., Jiang, H., et al. (2024). Study on preclinical safety and toxic mechanism of human umbilical cord mesenchymal stem cells in F344RG rats. Stem Cell Reviews and Reports, 20 (8), 2236–2252.

51. Marino, L., Castaldi, M. A., Rosamilio, R., Ragni, E., Vitolo, R., Fulgione, C. (2019). Mesenchymal stem cells from the wharton’s jelly of the human umbilical cord: biological properties and therapeutic potential. Int J Stem Cells , 3112 (2), 218–26.

52. Liau, L. L., Ruszymah, B. H. I., Ng, M. H., & Law, J. X. (2020). Characteristics and clinical applications of wharton’s jelly-derived mesenchymal stromal cells. Current Research in Translational Medicine, 68 (1), 5–16.

53. Kim, D. W., Staples, M., Shinozuka, K., Pantcheva, P., Kang, S. D., & Borlongan, C. V. (2013). Wharton’s jelly-derived mesenchymal stem cells: Phenotypic characterization and optimizing their therapeutic potential for clinical applications. International Journal of Molecular Sciences, 14 (6), 11692–11712.

54. Drobiova, H., Sindhu, S., Ahmad, R., Haddad, D., Al-Mulla, F., & Al Madhoun, A. (2023). Wharton’s jelly mesenchymal stem cells: A concise review of their secretome and prospective clinical applications. Frontiers in Cell and Developmental Biology, 11 , Article 1211217.

55. Zhang, J., Zhou, S., Zhou, Y., Feng, F., Wang, Q., Zhu, X., et al. (2016). Adipose-derived mesenchymal stem cells (ADSCs) with the potential to ameliorate platelet recovery, enhance megakaryopoiesis, and inhibit apoptosis of bone marrow cells in a mouse model of radiation-induced thrombocytopenia. Cell Transplantation, 25 (2), 261–273.

56. Cho, K. A., Kim, Y. H., Park, M., Kim, H. J., Woo, S. Y., Park, J. W., et al. (2019). Conditioned medium from human palatine tonsil mesenchymal stem cells attenuates acute graft–vs.–host disease in mice. Molecular Medicine Reports , 19 (1), 609–616.

57. Wang, Q., Xu, N., Wang, Y., Zhang, X., Liu, L., Zhou, H., et al. (2021). Allogeneic stem cell transplantation combined with transfusion of mesenchymal stem cells in primary myelofibrosis: A multicenter retrospective study. Frontiers in Oncology , 11 , 792142.

58. He, Y., Ji, D., Lu, W., Li, F., Huang, X., Huang, R., et al. (2021). Bone marrow mesenchymal stem cell-derived exosomes induce the Th17/Treg imbalance in immune thrombocytopenia through miR-146a-5p/IRAK1 axis. Human Cell, 34 (5), 1360–1374.

59. Ding, L., Han, D. M., Zheng, X. L., Yan, H. M., Xue, M., Liu, J., et al. (2021). A study of human leukocyte antigen-haploidentical hematopoietic stem cells transplantation combined with allogenic mesenchymal stem cell infusion for treatment of severe aplastic anemia in pediatric and adolescent patients. Stem Cells Translational Medicine, 10 (2), 291–302.

60. Huang, R., Chen, T., Wang, S., Wang, J., Su, Y., Liu, J., et al. (2024). Mesenchymal stem cells for prophylaxis of chronic graft-vs-host disease after haploidentical hematopoietic stem cell transplant: An open-label randomized clinical trial. JAMA Oncology, 10 (2), 220–226.

61. Ma, C., Feng, Y., Yang, L., Wang, S., Sun, X., Tai, S., et al. (2022). In vitro immunomodulatory effects of human umbilical cord-derived mesenchymal stem cells on peripheral blood cells from warm autoimmune hemolytic anemia patients. Acta Haematologica, 145 (1), 63–71.

62. Gholampour, M. A., Abroun, S., Nieuwland, R., Mowla, S. J., & Soudi, S. (2021). Mesenchymal stem cell-derived extracellular vesicles conditionally ameliorate bone marrow failure symptoms in an immune-mediated aplastic anemia mouse model. Journal of Cellular Physiology, 236 (8), 6055–6067.

63. Burnham, A. J., Foppiani, E. M., & Horwitz, E. M. (2020). Key metabolic pathways in MSC-mediated immunomodulation: Implications for the prophylaxis and treatment of graft versus host disease. Frontiers in Immunology, 11 , Article 609277.

64. Lim, J. Y., Ryu, D. B., Lee, S. E., Park, G., & Min, C. K. (2017). Mesenchymal stem cells (MSCs) attenuate cutaneous sclerodermatous graft-versus-host disease (scl-GVHD) through Inhibition of immune cell infiltration in a mouse model. The Journal of Investigative Dermatology , 137 (9), 1895–1904.

65. Towers, R., Trombello, L., Fusenig, M., Tunger, A., Baumann, A. L., Savoldelli, R., et al. (2024). Bone marrow-derived mesenchymal stromal cells obstruct AML-targeting CD8 + clonal effector and CAR T-cell function while promoting a senescence-associated phenotype. Cancer Immunology, Immunotherapy, 73 (1), Article 8.

66. Yuan, Y., Tan, S., Wang, H., Zhu, J., Li, J., Zhang, P., et al. (2023). Mesenchymal stem cell-derived exosomal miRNA-222-3p increases Th1/TH2 ratio and promotes apoptosis of acute myeloid leukemia cells. Analytical Cellular Pathology (Amsterdam), 2023 , Article 4024887.

67. Jiang, Y., Zhao, J., Wang, M., Huang, F., Li, J., Liu, R., et al. (2023). Mesenchymal stem cell-derived exosomes can alleviate GVHD and preserve the GVL effect in allogeneic stem cell transplantation animal models. Frontiers in Immunology, 14 , Article 1284936.

68. Liu, W., Zhou, N., Liu, Y., Zhang, W., Li, X., Wang, Y., et al. (2021). Mesenchymal stem cell exosome-derived miR-223 alleviates acute graft-versus-host disease via reducing the migration of donor T cells. Stem Cell Research & Therapy , 12 (1), 153.

69. Zhou, X., Jin, N., Wang, F., & Chen, B. (2020). Mesenchymal stem cells: A promising way in therapies of graft-versus-host disease. Cancer Cell International, 20 , Article 114.

70. Mahmoudi, M., Taghavi-Farahabadi, M., Namaki, S., Baghaei, K., Rayzan, E., Rezaei, N., et al. (2019). Exosomes derived from mesenchymal stem cells improved function and survival of neutrophils from severe congenital neutropenia patients in vitro. Human Immunology, 80 (12), 990–998.

71. Taghavi-Farahabadi, M., Mahmoudi, M., Hashemi, S. M., & Rezaei, N. (2020). Evaluation of the effects of mesenchymal stem cells on neutrophils isolated from severe congenital neutropenia patients. International Immunopharmacology, 83 , Article 106463.

72. Broglie, L., Margolis, D., & Medin, J. A. (2017). Yin and yang of mesenchymal stem cells and aplastic anemia. World Journal of Stem Cells, 9 (12), 219–226.

73. Singh, A. K., Prasad, P., & Cancelas, J. A. (2023). Mesenchymal stromal cells, metabolism, and mitochondrial transfer in bone marrow normal and malignant hematopoiesis. Frontiers in Cell and Developmental Biology, 11 , Article 1325291.

74. Forte, D., García-Fernández, M., Sánchez-Aguilera, A., Stavropoulou, V., Fielding, C., Martín-Pérez, D., et al. (2020). Bone marrow mesenchymal stem cells support acute myeloid leukemia bioenergetics and enhance antioxidant defense and escape from chemotherapy. Cell Metabolism, 32 (5), 829-843e9.

75. Moschoi, R., Imbert, V., Nebout, M., Chiche, J., Mary, D., Prebet, T. (2016). Protective mitochondrial transfer from bone marrow stromal cells to acute myeloid leukemic cells during chemotherapy. Blood, 128 (2), 253–264.

76. Sandhow, L., Cai, H., Leonard, E., Xiao, P., Tomaipitinca, L., Månsson, A., et al. (2023). Skin mesenchymal niches maintain and protect AML-initiating stem cells. Journal of Experimental Medicine, 220 (10), Article e20220953.

77. Yang, H., Cheong, S., He, Y., & Lu, F. (2023). Mesenchymal stem cell-based therapy for autoimmune-related fibrotic skin diseases-systemic sclerosis and sclerodermatous graft-versus-host disease. Stem Cell Research & Therapy , 14 (1), 372.

78. Frangogiannis, N. (2020). Transforming growth factor-β in tissue fibrosis. Journal of Experimental Medicine, 217 (3), Article e20190103.

79. Han, Y., Yang, J., Fang, J., Zhou, Y., Candi, E., Wang, J., et al. (2022). The secretion profile of mesenchymal stem cells and potential applications in treating human diseases. Signal Transduction and Targeted Therapy, 7 (1), Article 92.

80. Su, Y., Xu, C., Cheng, W., Zhao, Y., Sui, L., & Zhao, Y. (2023). Pretreated mesenchymal stem cells and their secretome: Enhanced immunotherapeutic strategies. International Journal of Molecular Sciences, 24 (2), Article 1277.

81. Malekpour, K., Hazrati, A., Soudi, S., & Hashemi, S. M. (2023). Mechanisms behind therapeutic potentials of mesenchymal stem cell mitochondria transfer/delivery. Journal of Controlled Release, 354 , 755–769.

82. Trigo, C. M., Rodrigues, J. S., Camões, S. P., Solá, S., & Miranda, J. P. (2024). Mesenchymal stem cell secretome for regenerative medicine: Where do we stand? Journal of Advanced Research , S2090-1232 (24), 181–184.

83. Zhang, Y., Wu, D., Zhou, C., Bai, M., Wan, Y., Zheng, Q., et al. (2024). Engineered extracellular vesicles for tissue repair and regeneration. Burns & Trauma, 12 , Article tkae062.

84. Wu, C. H., Weng, T. F., Li, J. P., & Wu, K. H. (2024). Biology and therapeutic properties of mesenchymal stem cells in leukemia. International Journal of Molecular Sciences, 25 (5), Article 2527.

85. Sarmadi, V. H., Ahmadloo, S., Boroojerdi, M. H., John, C. M., Al-Graitte, S. J. R., Lawal, H., et al. (2020). Human mesenchymal stem cells-mediated transcriptomic regulation of leukemic cells in delivering anti-tumorigenic effects. Cell Transplantation, 29 , Article 963689719885077.

86. Borella, G., Da Ros, A., Borile, G., Porcù, E., Tregnago, C., Benetton, M., et al. (2021). Targeting the plasticity of mesenchymal stromal cells to reroute the course of acute myeloid leukemia. Blood , 138 (7), 557–570.

87. Chowdhury, A., Loaiza, S., Yebra-Fernandez, E., Nadal-Melsio, E., Apperley, J. F., & Khorashad, J. S. (2020). An ex vivo investigation of interactions between primary acute myeloid leukaemia and mesenchymal stromal cells yields novel therapeutic targets. British Journal of Haematology, 190 (4), Article e236–e239.

88. Lyu, T., Zhang, B., Li, M., Jiao, X., & Song, Y. (2021). Research progress on exosomes derived from mesenchymal stem cells in hematological malignancies. Hematological Oncology, 39 (2), 162–169.

89. Jiang, D., Wu, X., Sun, X., Tan, W., Dai, X., Xie, Y., et al. (2022). Bone mesenchymal stem cell-derived Exosomal microRNA-7-5p inhibits progression of acute myeloid leukemia by targeting OSBPL11. J Nanobiotechnology , 20 (1), 29.

90. Zhang, F., Lu, Y., Wang, M., Zhu, J., Li, J., Zhang, P., et al. (2020). Exosomes derived from human bone marrow mesenchymal stem cells transfer miR-222-3p to suppress acute myeloid leukemia cell proliferation by targeting IRF2/INPP4B. Molecular and Cellular Probes, 51 , Article 101513.

91. Cheng, H., Ding, J., Tang, G., Huang, A., Gao, L., Yang, J., et al. (2021). Human mesenchymal stem cells derived exosomes inhibit the growth of acute myeloid leukemia cells via regulating miR-23b-5p/TRIM14 pathway. Molecular Medicine, 27 (1), Article 128.

92. Xu, Y. C., Lin, Y. S., Zhang, L., Lu, Y., Sun, Y. L., Fang, Z. G., et al. (2020). MicroRNAs of bone marrow mesenchymal stem cell-derived exosomes regulate acute myeloid leukemia cell proliferation and apoptosis. Chinese Medical Journal, 133 (23), 2829–2839.

93. Wang, F. (2024). Mechanism of bone-marrow mesenchymal stem cell-derived exosomes mediating microRNA-139-5p to regulate β-catenin in the modulation of proliferation and apoptosis of acute myeloid leukemia cells. Hematology, 29 (1), Article 2428482.

94. Jalilivand, S., Izadirad, M., Vazifeh Shiran, N., Gharehbaghian, A., & Naserian, S. (2024). The effect of bone marrow mesenchymal stromal cell exosomes on acute myeloid leukemia’s biological functions: A focus on the potential role of LncRNAs. Clinical and Experimental Medicine, 24 (1), Article 108.

95. Lee, M. W., Ryu, S., Kim, D. S., Lee, J. W., Sung, K. W., Koo, H. H., et al. (2019). Mesenchymal stem cells in suppression or progression of hematologic malignancy: Current status and challenges. Leukemia, 33 (3), 597–611.

96. Giallongo, S., Duminuco, A., Dulcamare, I., Zuppelli, T., La Spina, E., Scandura, G., et al. (2023). Engagement of mesenchymal stromal cells in the remodeling of the bone marrow microenvironment in hematological cancers. Biomolecules, 13 (12), Article 1701.

97. Ma, Z., Zhao, X., Deng, M., Huang, Z., Wang, J., Wu, Y., et al. (2019). Bone marrow mesenchymal stromal cell-derived periostin promotes B-ALL progression by modulating CCL2 in leukemia cells. Cell Reports, 26 (6), 1533-1543e4.

98. Guo, J., Zhao, Y., Fei, C., Zhao, S., Zheng, Q., Su, J., et al. (2018). Dicer1 downregulation by multiple myeloma cells promotes the senescence and tumor-supporting capacity and decreases the differentiation potential of mesenchymal stem cells. Cell Death and Disease, 9 (5), Article 512.

99. Zhong, W., Zhu, Z., Xu, X., Zhang, H., Xiong, H., Li, Q., et al. (2019). Human bone marrow-derived mesenchymal stem cells promote the growth and drug-resistance of diffuse large B-cell lymphoma by secreting IL-6 and elevating IL-17A levels. Journal of Experimental & Clinical Cancer Research, 38 (1), Article 73.

100. Zhang, X., Tu, H., Yang, Y., Jiang, X., Hu, X., Luo, Q., et al. (2019). Bone marrow-derived mesenchymal stromal cells promote resistance to tyrosine kinase inhibitors in chronic myeloid leukemia via the IL-7/JAK1/STAT5 pathway. Journal of Biological Chemistry, 294 (32), 12167–12179.

101. McNee, G., Eales, K. L., Wei, W., Williams, D. S., Barkhuizen, A., Bartlett, D. B., et al. (2017). Citrullination of histone H3 drives IL-6 production by bone marrow mesenchymal stem cells in MGUS and multiple myeloma. Leukemia, 31 (2), 373–381.

102. Feng, X., Sun, R., Lee, M., Chen, X., Guo, S., Geng, H., et al. (2023). Cell circuits between leukemic cells and mesenchymal stem cells block lymphopoiesis by activating lymphotoxin beta receptor signaling. eLife, 12 , Article e83533.

103. Sherman, L. S., Patel, S. A., Castillo, M. D., Unkovic, R., Taborga, M., Gergues, M., et al. (2021). NFĸB targeting in bone marrow mesenchymal stem cell-mediated support of age-linked hematological malignancies. Stem Cell Reviews and Reports, 17 (6), 2178–2192.

104. Zheng, L., Pan, C., Ma, D., Shang, Q., Hu, T., Zhang, T., et al. (2024). Overexpression of Nrf2 in bone marrow mesenchymal stem cells promotes B-cell acute lymphoblastic leukemia cells invasion and extramedullary organ infiltration through stimulation of the SDF-1/CXCR4 axis. Frontiers in Pharmacology, 15 , Article 1393482.

105. Zahedpanah, M., Takanlu, J. S., Nikbakht, M., Rad, F., Farhid, F., Mousavi, S. A., et al. (2019). Microvesicles of osteoblasts modulate bone marrow mesenchymal stem cell-induced apoptosis to curcumin in myeloid leukemia cells. Journal of Cellular Physiology, 234 (10), 18707–18719.

106. L Z, H. L. J. L. J. C. X. C. Z L. (2019). AML–derived mesenchymal stem cells upregulate CTGF expression through the BMP pathway and induce K562–ADM fusiform transformation and chemoresistance. Oncology Reports, 2019 42(3). [Internet] Available from: https://pubmed.ncbi.nlm.nih.gov/31322275/

107. Cheng, J., Li, Y., Liu, S., Jiang, Y., Ma, J., Wan, L., et al. (2019). CXCL8 derived from mesenchymal stromal cells supports survival and proliferation of acute myeloid leukemia cells through the PI3K/AKT pathway. The FASEB Journal, 33 (4), 4755–4764.

108. Jiang, Y., Li, Y., Cheng, J., Ma, J., Li, Q., & Pang, T. (2020). Upregulation of AKR1C1 in mesenchymal stromal cells promotes the survival of acute myeloid leukaemia cells. British Journal of Haematology, 189 (4), 694–706.

109. Li, Y., Jiang, Y., Cheng, J., Ma, J., Li, Q., & Pang, T. (2020). ATG5 regulates mesenchymal stem cells differentiation and mediates chemosensitivity in acute myeloid leukemia. Biochemical And Biophysical Research Communications, 525 (2), 398–405.

110. Lu, J., Dong, Q., Zhang, S., Feng, Y., Yang, J., & Zhao, L. (2023). Acute myeloid leukemia (AML)-derived mesenchymal stem cells induce chemoresistance and epithelial-mesenchymal transition-like program in AML through IL-6/JAK2/STAT3 signaling. Cancer Science, 114 (8), 3287–3300.

111. Rethnam, M., Tan, D. Q., & Suda, T. (2021). Myeloma cells self-promote migration by regulating tables 1-driven TIMP-1 expression in mesenchymal stem cells. Biochemical and Biophysical Research Communications, 534 , 843–848.

112. Li, K., Nie, H., Jin, R., & Wu, X. (2024). Mesenchymal stem cells-macrophages crosstalk and myeloid malignancy. Frontiers in Immunology, 15 , Article 1397005.

113. Jafarzadeh, N., Safari, Z., Pornour, M., Amirizadeh, N., Forouzandeh Moghadam, M., & Sadeghizadeh, M. (2019). Alteration of cellular and immune-related properties of bone marrow mesenchymal stem cells and macrophages by K562 chronic myeloid leukemia cell derived exosomes. Journal of Cellular Physiology, 234 (4), 3697–3710.

114. Alameda, D., Saez, B., Lara-Astiaso, D., Sarvide, S., Lasa, M., Alignani, D. (2020). Characterization of freshly isolated bone marrow mesenchymal stromal cells from healthy donors and patients with multiple myeloma: transcriptional modulation of the microenvironment. Haematologica, 105(9), e470-473.

115. Liu, Z., Guo, Y., Huang, L., Jia, Y., Liu, H., Peng, F., et al. (2022). Bone marrow mesenchymal stem cells regulate the dysfunction of NK cells via the T cell immunoglobulin and ITIM domain in patients with myelodysplastic syndromes. Cell Communication and Signaling, 20 (1), Article 169.

116. Chen, D., Tang, P., Liu, L., Wang, F., Xing, H., Sun, L., et al. (2018). Bone marrow-derived mesenchymal stem cells promote cell proliferation of multiple myeloma through inhibiting T cell immune responses via PD-1/PD-L1 pathway. Cell Cycle, 17 (7), 858–867.

117. de Freitas, F. A., Levy, D., Reichert, C. O., Sampaio-Silva, J., Giglio, P. N., de Pádua Covas Lage, L. A., et al. (2024). Influence of human bone marrow mesenchymal stem cells secretome from acute myeloid leukemia patients on the proliferation and death of K562 and K562-lucena leukemia cell lineages. International Journal of Molecular Sciences, 25 (9), Article 4748.

118. Gao, X., Zhou, J., Wang, J., Dong, X., Chang, Y., & Jin, Y. (2021). Mechanism of exosomal miR-155 derived from bone marrow mesenchymal stem cells on stemness maintenance and drug resistance in myeloma cells. Journal Of Orthopaedic Surgery And Research, 16 (1), Article 637.

119. Xu, R., Huang, X., Li, C., Deng, C., Li, M., Wu, P., et al. (2021). Bone marrow mesenchymal stromal cells in chronic myelomonocytic leukaemia: Overactivated WNT/β-catenin signalling by parallel RNA sequencing and dysfunctional phenotypes. British Journal of Haematology, 193 (5), 928–940.

120. Pan, C., Liu, P., Ma, D., Zhang, S., Ni, M., Fang, Q., et al. (2020). Bone marrow mesenchymal stem cells in microenvironment transform into cancer-associated fibroblasts to promote the progression of B-cell acute lymphoblastic leukemia. Biomedicine & Pharmacotherapy, 130 , Article 110610.

121. Cheng, Q., Li, X., Liu, J., Ye, Q., Chen, Y., & Tan, S. (2017). Multiple myeloma-derived exosomes regulate the functions of mesenchymal stem cells partially via modulating miR-21 and miR-146a. Stem Cells International, 2017 , Article 9012152.

122. Zhang, L., Zhao, Q., Cang, H., Wang, Z., Hu, X., & Pan, R. (2022). Acute myeloid leukemia cells educate mesenchymal stromal cells toward an adipogenic differentiation propensity with leukemia promotion capabilities. Advanced Science, 9 (16), Article 2105811.

123. Raimondo, S., Urzì, O., Conigliaro, A., Bosco, G. L., Parisi, S., Carlisi, M., et al. (2020). Extracellular vesicle microRNAs contribute to the osteogenic inhibition of mesenchymal stem cells in multiple myeloma. Cancers, 12 (2), Article 449.

124. Chetty, V. K., Ghanam, J., Lichá, K., Brenzel, A., Reinhardt, D., & Thakur, B. K. (2024). Y-box binding protein 1 in small extracellular vesicles reduces mesenchymal stem cell differentiation to osteoblasts-implications for acute myeloid leukaemia. Journal of Extracellular Vesicles, 13 (3), Article e12417.

125. Pan, C., Fang, Q., Liu, P., Ma, D., Cao, S., Zhang, L., et al. (2021). Mesenchymal stem cells with cancer-associated fibroblast-like phenotype stimulate SDF-1/CXCR4 axis to enhance the growth and invasion of B-cell acute lymphoblastic leukemia cells through cell-to-cell communication. Frontiers in Cell and Developmental Biology, 9 , Article 708513.

126. Wang, Y., Fang, J., Liu, B., Shao, C., & Shi, Y. (2022). Reciprocal regulation of mesenchymal stem cells and immune responses. Cell Stem Cell, 29 (11), 1515–1530.

127. Åhsberg, J., Xiao, P., Okuyama, K., Somasundaram, R., Strid, T., Qian, H., et al. (2020). Progression of progenitor B-cell leukemia is associated with alterations of the bone marrow micro-environment. Haematologica, 105 (3), Article e102–e106.

128. Xiao, P., Sandhow, L., Heshmati, Y., Kondo, M., Bouderlique, T., Dolinska, M. (2018) Distinct roles of mesenchymal stem and progenitor cells during the development of acute myeloid leukemia in mice. Blood Adv, 2 (12), 1480–1494.

129. Orange, S. T., Leslie, J., Ross, M., Mann, D. A., & Wackerhage, H. (2023). The exercise IL-6 enigma in cancer. Trends in Endocrinology and Metabolism, 34 (11), 749–763.

130. Anastasiadou, D. P., Quesnel, A., Duran, C. L., Filippou, P. S., & Karagiannis, G. S. (2024). An emerging paradigm of CXCL12 involvement in the metastatic cascade. Cytokine & Growth Factor Reviews , 75 , 12–30.

131. Fry, T. J., & Mackall, C. L. (2005). The many faces of IL-7: fom lymphopoiesis to peripheral T cell maintenance. J Immunol , 174 (11), 6571–6.

132. Antoon, R., Overdevest, N., Saleh, A. H., & Keating, A. (2024). Mesenchymal stromal cells as cancer promoters. Oncogene, 43 (49), 3545–3555.

133. Kim, A., Shim, S., Kim, M. J., Myung, J. K., & Park, S. (2018). Mesenchymal stem cell-mediated NotcH2 activation overcomes radiation-induced injury of the hematopoietic system. Scientific Reports, 18 (1), Article 9277.

134. Vallabhaneni, K. C., Hassler, M. Y., Abraham, A., Whitt, J., Mo, Y. Y., Atfi, A., et al. (2016). Mesenchymal stem/stromal cells under stress increase osteosarcoma migration and apoptosis resistance via extracellular vesicle mediated communication. PLoS One, 11 (11), Article e0166027.

135. Wang, Y. (2021). Mesenchymal stem cells (MSC) delays the occurrence of graft-versus-host disease(GVHD) in the inhibition of hematopoietic stem cells in major histocompatibility complex semi-consistent mice by regulating the expression of IFN-γ/IL-6. Bioengineered, 12 (1), 4500–4507.

136. Lim, J., Heo, J., Ju, H., Shin, J. W., Kim, Y., Lee, S., et al. (2020). Glutathione dynamics determine the therapeutic efficacy of mesenchymal stem cells for graft-versus-host disease via CREB1-NRF2 pathway. Science Advances, 6 (16), Article eaba1334.

137. Lim, J., Heo, J., Yu, H. Y., Yun, H., Lee, S., Ju, H., et al. (2021). Small-sized mesenchymal stem cells with high glutathione dynamics show improved therapeutic potency in graft-versus-host disease. Clinical and Translational Medicine, 11 (7), Article e476.

138. Hinden, L., Avner, M., Stepensky, P., Or, R., & Almogi-Hazan, O. (2019). Lymphocyte counts may predict a good response to mesenchymal stromal cells therapy in graft versus host disease patients. PLoS One, 14 (6), Article e0217572.

139. Shen, M. Z., Liu, X. X., Qiu, Z. Y., Xu, L. P., Zhang, X. H., Wang, Y., et al. (2022). Efficacy and safety of mesenchymal stem cells treatment for multidrug-resistant graft-versus-host disease after haploidentical allogeneic hematopoietic stem cell transplantation. Therapeutic Advances in Hematology, 13 , Article 20406207211072838.

140. Krasowska-Kwiecien, A., Gozdzik, J., Jarocha, D., Wozniak, M., Czogala, W., Wiecha, O., et al. (2019). Mesenchymal stem cells as a salvage treatment for severe refractory graft-vs-host disease in children after bone marrow transplantation. Transplantation Proceedings, 51 (3), 880–889.

141. Stenger, E., Giver, C. R., Langston, A., Kota, D., Das, P. K., Chinnadurai, R., et al. (2022). Safety of autologous freshly expanded mesenchymal stromal cells for the treatment of graft-versus-host disease. Frontiers in Immunology, 13 , Article 959658.

142. Murata, M., Terakura, S., Wake, A., Miyao, K., Ikegame, K., Uchida, N., et al. (2021). Off-the-shelf bone marrow-derived mesenchymal stem cell treatment for acute graft-versus-host disease: Real-world evidence. Bone Marrow Transplantation, 56 (10), 2355–2366.

143. Stoma, I., Karpov, I., Krivenko, S., Iskrov, I., Milanovich, N., Koritko, A., et al. (2018). Mesenchymal stem cells transplantation in hematological patients with acute graft-versus-host disease: Characteristics and risk factors for infectious complications. Annals Of Hematology, 97 (5), 885–891.

144. Bader, P., Kuçi, Z., Bakhtiar, S., Basu, O., Bug, G., Dennis, M., et al. (2018). Effective treatment of steroid and therapy-refractory acute graft-versus-host disease with a novel mesenchymal stromal cell product (MSC-FFM). Bone Marrow Transplantation, 53 (7), 852–862.

145. Bonig, H., Kuçi, Z., Kuçi, S., Bakhtiar, S., Basu, O., Bug, G., et al. (2019). Children and adults with refractory acute graft-versus-host disease respond to treatment with the mesenchymal stromal cell preparation MSC-FFM-outcome report of 92 patients. Cells, 8 (12), Article 1577.

146. Bonig, H., Verbeek, M., Herhaus, P., Braitsch, K., Beutel, G., Schmid, C., et al. (2023). Real-world data suggest effectiveness of the allogeneic mesenchymal stromal cells preparation MSC-FFM in ruxolitinib-refractory acute graft-versus-host disease. Journal Of Translational Medicine, 21 (1), Article 837.

147. Kubota, H., Arakawa, Y., Mizushima, Y., Irikura, T., Watakabe, M., Ishikawa, T., et al. (2024). Efficacy of off-the-shelf bone marrow mesenchymal stem cells for pediatric steroid-refractory acute graft-versus-host disease. Blood Cell Ther , 7 (1), 1–9.

148. van der Wagen, L. E., Miranda-Bedate, A., Janssen, A., Fernando, F., Appukudige, N., van Dooremalen, S., et al. (2020). Efficacy of MSC for steroid-refractory acute GVHD associates with MSC donor age and a defined molecular profile. Bone Marrow Transplantation , 55 (11), 2188–2192.

149. Jiang, E., Qian, K., Wang, L., Yang, D., Shao, Y., Hu, L., et al. (2024). Efficacy and safety of human umbilical cord-derived mesenchymal stem cells versus placebo added to second-line therapy in patients with steroid-refractory acute graft-versus-host disease: A multicentre, randomized, double-blind, phase 2 trial. BMC Medicine, 22 (1), Article 555.

150. Bozkurt, C., Karaöz, E., Adaklı Aksoy, B., Aydoğdu, S., & Fışgın, T. (2019). The use of allogeneic mesenchymal stem cells in childhood steroid-resistant acute graft-versus-host disease: A retrospective study of a single-center experience. Turk J Haematol: Off J Turk Soc Haematol, 36 (3), 186–192.

151. Zu, Y., Zhou, J., Fu, Y., Fang, B., Liu, X., Zhang, Y., et al. (2021). Feasibility of reduced-dose posttransplant cyclophosphamide and cotransplantation of peripheral blood stem cells and umbilical cord-derived mesenchymal stem cells for SAA. Scientific Reports, 11 (1), Article 253.

152. Lan, Y., Liu, F., Chang, L., Liu, L., Zhang, Y., Yi, M., et al. (2021). Combination of umbilical cord mesenchymal stem cells and standard immunosuppressive regimen for pediatric patients with severe aplastic anemia. BMC Pediatrics, 21 (1), Article 102.

153. Liu, Z., Zhang, Y., Xiao, H., Yao, Z., Zhang, H., Liu, Q., et al. (2017). Cotransplantation of bone marrow-derived mesenchymal stem cells in haploidentical hematopoietic stem cell transplantation in patients with severe aplastic anemia: An interim summary for a multicenter phase II trial results. Bone Marrow Transplantation, 52 (5), 704–710.

154. Zhang, Y., Zheng, H., Ren, J., Luo, X., Zheng, Z., Zheng, J., et al. (2021). Mesenchymal stem cells enhance the impact of KIR receptor-ligand mismatching on acute graft-versus-host disease following allogeneic hematopoietic stem cell transplantation in patients with acute myeloid leukemia but not in those with acute lymphocytic leukemia. Hematological Oncology, 39 (3), 380–389.

155. Wang, X., Zhang, M., & He, P. (2020). Pre-infusion single-dose mesenchymal stem cells promote platelet engraftment and decrease severe acute graft versus host disease without relapse in haploidentical peripheral blood stem cell transplantation. Journal of International Medical Research, 48 (5), Article 300060520920438.

156. Rostami, T., Maleki, N., Kasaeian, A., Nikbakht, M., Kiumarsi, A., Asadollah Mousavi, S., et al. (2021). Co-transplantation of bone marrow-derived mesenchymal stem cells with hematopoietic stem cells does not improve transplantation outcome in class III beta-thalassemia major: A prospective cohort study with long-term follow-up. Pediatric Transplantation, 25 (3), Article e13905.

157. Rostami, T., Kasaeian, A., Maleki, N., Nikbakht, M., Kiumarsi, A., Tavangar, S. M., et al. (2021). The effect of bone marrow-derived mesenchymal stem cell co-transplantation with hematopoietic stem cells on liver fibrosis alleviation and survival in patients with class III β-thalassemia major. Stem Cell Research & Therapy , 12 (1), 213.

158. Lu, W., & Allickson, J. (2025 June). Mesenchymal stromal cell therapy: progress to date and future outlook. Mol Ther: J Am Soc Gene Ther , 4 (6), 2679–2688.

159. Fisher, S. A., Cutler, A., Doree, C., Brunskill, S. J., Stanworth, S. J., Navarrete, C., et al. (2019). Mesenchymal stromal cells as treatment or prophylaxis for acute or chronic graft-versus-host disease in Haematopoietic stem cell transplant (HSCT) recipients with a haematological condition. Cochrane Database Systematic Review , 1 (1), CD009768.

160. Li, Y., Hao, J., Hu, Z., Yang, Y. G., Zhou, Q., Sun, L., et al. (2022). Current status of clinical trials assessing mesenchymal stem cell therapy for graft versus host disease: A systematic review. Stem Cell Research & Therapy , 13 (1), 93.

161. Qian, H., Le Blanc, K., & Sigvardsson, M. (2012). Primary mesenchymal stem and progenitor cells from bone marrow lack expression of CD44 protein. J Biol Chem, 287(31), 25795–25807.

162. Zhou, L., Liu, S., Wang, Z., Yao, J., Cao, W., Chen, S., et al. (2019). Bone marrow-derived mesenchymal stem cells modified with Akt1 ameliorates acute liver GVHD. Biological Procedures Online, 21 , Article 24.

163. Kim, Y., Jin, H. J., Heo, J., Ju, H., Lee, H. Y., Kim, S., et al. (2018). Small hypoxia-primed mesenchymal stem cells attenuate graft-versus-host disease. Leukemia , 32 (12), 2672–2684.

164. Silva-Carvalho, A. É., Rodrigues, L. P., Schiavinato, J. L., Alborghetti, M. R., Bettarello, G., Simões, B. P., et al. (2020). GVHD-derived plasma as a priming strategy of mesenchymal stem cells. Stem Cell Research & Therapy , 11 (1), 156.

165. Gupta, M., Tieu, A., Slobodian, M., Shorr, R., Burger, D., Lalu, M. M., et al. (2021). Preclinical studies of MSC-derived extracellular vesicles to treat or prevent graft versus host disease: A systematic review of the literature. Stem Cell Reviews And Reports, 17 (2), 332–340.

166. Li, K. L., Li, J. Y., Xie, G. L., & Ma, X. Y. (2021). Exosomes released from human bone marrow-derived mesenchymal stem cell attenuate acute graft-versus-host disease after allogeneic hematopoietic stem cell transplantation in mice. Frontiers in Cell and Developmental Biology, 9 , Article 617589.

167. Dorofeeva, A. I., Shipounova, I. N., Nikiforova, K. A., Galtseva, I. V., Kuzmina, L. A., Luchkin, A. V., et al. (2024). PDGF-BB deficiency in the blood serum from aplastic anemia patients affects bone marrow-derived multipotent mesenchymal stromal cells. Cells, 13 (22), Article 1908.

168. Lu, S., Ge, M., Zheng, Y., Li, J., Feng, X., Feng, S., et al. (2017). CD106 is a novel mediator of bone marrow mesenchymal stem cells via NF-κB in the bone marrow failure of acquired aplastic anemia. Stem Cell Research & Therapy , 8 (1), 178.

169. Li, S., Qin, M., Wu, R., Meng, H., He, Y., Wang, B., et al. (2020). Insensitive to PTH of CD8 + T cells regulate bone marrow mesenchymal stromal cell in aplastic anemia patients. International Journal of Medical Sciences, 17 (12), 1665–1672.

170. Li, H., Xu, X., Wang, D., Zeng, L., Li, B., Zhang, Y., et al. (2020). MiR-146b-5p regulates bone marrow mesenchymal stem cell differentiation by SIAH2/PPARγ in aplastic anemia children and benzene-induced aplastic anemia mouse model. Cell Cycle, 19 (19), 2460–2471.

171. Li, H., Xu, X., Wang, D., Zhang, Y., Chen, J., Li, B., et al. (2021). Hypermethylation-mediated downregulation of long non-coding RNA MEG3 inhibits osteogenic differentiation of bone marrow mesenchymal stem cells and promotes pediatric aplastic anemia. International Immunopharmacology, 93 , Article 107292.

172. Peng, Y. H., Li, C. W., Wu, K. H., Li, J. P., Yang, S. F., & Chao, Y. H. (2024). Up-regulated expression of thioredoxin-interacting protein (TXNIP) in mesenchymal stem cells associated with severe aplastic anemia in children. International Journal of Molecular Sciences, 25 (22), Article 12298.

173. Chao, Y. H., Lin, C. W., Pan, H. H., Yang, S. F., Weng, T. F., Peng, C. T., et al. (2018). Increased apoptosis and peripheral blood mononuclear cell suppression of bone marrow mesenchymal stem cells in severe aplastic anemia. Pediatric Blood & Cancer 65 (9), e27247.

174. Li, J. P., Wu, K. H., Chao, W. R., Lee, Y. J., Yang, S. F., & Chao, Y. H. (2023). Alterations of mesenchymal stem cells on regulating Th17 and Treg differentiation in severe aplastic anemia. Aging, 15 (2), 553–566.

175. Li, Y., Wang, F., Guo, R., Zhang, Y., Chen, D., Li, X., et al. (2019). Exosomal sphingosine 1-phosphate secreted by mesenchymal stem cells regulated treg/Th17 balance in aplastic anemia. IUBMB Life, 71 (9), 1284–1292.

176. Srivastava, J., Kundal, K., Rai, B., Saxena, P., Katiyar, S., Tripathy, N., et al. (2024). Global MicroRNA profiling of bone marrow-MSC derived extracellular vesicles identifies miRNAs associated with hematopoietic dysfunction in aplastic anemia. Scientific Reports, 14 (1), Article 19654.

177. Wang, S., Huo, J., Liu, Y., Chen, L., Ren, X., Li, X., et al. (2023). Impaired immunosuppressive effect of bone marrow mesenchymal stem cell-derived exosomes on T cells in aplastic anemia. Stem Cell Research & Therapy , 14 (1), 285.

178. Wei, Y., Zhang, L., Chi, Y., Ren, X., Gao, Y., Song, B., et al. (2020). High-efficient generation of VCAM-1 + mesenchymal stem cells with multidimensional superiorities in signatures and efficacy on aplastic anaemia mice. Cell Proliferation, 53 (8), Article e12862.

179. Wang, Z. K., Yu, H. J., Cao, F. L., Liu, Z. H., Liu, Z. Y., Feng, W. J., et al. (2019). Donor-derived marrow mesenchymal stromal cell co-transplantation following a haploidentical hematopoietic stem cell transplantation trail to treat severe aplastic anemia in children. Annals of Hematology , 98 (2), 473–479.

180. Xu, L. L., Fu, H. X., Zhang, J. M., Feng, F. E., Wang, Q. M., Zhu, X. L., et al. (2017). Impaired function of bone marrow mesenchymal stem cells from immune thrombocytopenia patients in inducing regulatory dendritic cell differentiation through the Notch-1/Jagged-1 signaling pathway. Stem Cells and Development, 26 (22), 1648–1661.

181. Wang, M., Feng, R., Zhang, J. M., Xu, L. L., Feng, F. E., Wang, C. C., et al. (2019). Dysregulated megakaryocyte distribution associated with nestin + mesenchymal stem cells in immune thrombocytopenia. Blood Advances, 3 (9), 1416–1428.

182. He, Y., Xu, L. L., Feng, F. E., Wang, Q. M., Zhu, X. L., Wang, C. C., et al. (2018). Mesenchymal stem cell deficiency influences megakaryocytopoiesis through the TNFAIP3/NF-κB/SMAD pathway in patients with immune thrombocytopenia. British Journal of Haematology, 180 (3), 395–411.

183. Zhu, X., Wang, Y., Jiang, Q., Jiang, H., Lu, J., Wang, Y., et al. (2019). All-trans retinoic acid protects mesenchymal stem cells from immune thrombocytopenia by regulating the complement-interleukin-1β loop. Haematologica, 104 (8), 1661–1675.

184. Zhang, J. M., Feng, F. E., Wang, Q. M., Zhu, X. L., Fu, H. X., Xu, L. P., et al. (2016). Platelet-derived growth factor-BB protects mesenchymal stem cells (MSCs) derived from immune thrombocytopenia patients against apoptosis and senescence and maintains MSC-mediated immunosuppression. Stem Cells Translational Medicine, 5 (12), 1631–1643.

185. Wang, X., Yin, X., Sun, W., Bai, J., Shen, Y., Ao, Q., et al. (2017). Intravenous infusion umbilical cord-derived mesenchymal stem cell in primary immune thrombocytopenia: A two-year follow-up. Experimental And Therapeutic Medicine, 13 (5), 2255–2258.

186. Zheng, L., Zhang, L., Guo, Y., Xu, X., Liu, Z., Yan, Z., et al. (2022). The immunological role of mesenchymal stromal cells in patients with myelodysplastic syndrome. Frontiers in Immunology, 13 , Article 1078421.

187. Qu, B., Han, X., Zhao, L., Zhang, F., & Gao, Q. (2022). Relationship of HIF–1α expression with apoptosis and cell cycle in bone marrow mesenchymal stem cells from patients with myelodysplastic syndrome. Molecular Medicine Reports , 26 (1), 239.

188. Eroz, I., Kakkar, P. K., Lazar, R. A., & El-Jawhari, J. (2014). Mesenchymal stem cells in myelodysplastic syndromes and leukaemia. Biomedicines , 12 (8), 1677.

189. Giallongo, C., Dulcamare, I., Giallongo, S., Duminuco, A., Pieragostino, D., Cufaro, M. C., et al. (2023). MacroH2A1.1 as a crossroad between epigenetics, inflammation and metabolism of mesenchymal stromal cells in myelodysplastic syndromes. Cell Death and Disease, 14 (10), Article 686.

190. Sarhan, D., Wang, J., Sunil Arvindam, U., Hallstrom, C., Verneris, M. R., Grzywacz, B., et al. (2020). Mesenchymal stromal cells shape the MDS microenvironment by inducing suppressive monocytes that dampen NK cell function. JCI Insight, 5 (5), Article e130155.

191. Meunier, M., Guttin, A., Ancelet, S., Laurin, D., Zannoni, J., Lefebvre, C., et al. (2020). Extracellular vesicles from myelodysplastic mesenchymal stromal cells induce DNA damage and mutagenesis of hematopoietic stem cells through miRNA transfer. Leukemia, 34 (8), 2249–2253.

192. Wobus, M., Mies, A., Asokan, N., Oelschlägel, U., Möbus, K., Winter, S., et al. (2021). Luspatercept restores SDF-1-mediated hematopoietic support by MDS-derived mesenchymal stromal cells. Leukemia, 35 (10), 2936–2947.

193. Sabbah, R., Saadi, S., Shahar-Gabay, T., Gerassy, S., Yehudai-Resheff, S., & Zuckerman, T. (2023). Abnormal adipogenic signaling in the bone marrow mesenchymal stem cells contributes to supportive microenvironment for leukemia development. Cell Communication and Signaling, 21 (1), Article 277.

194. Phetfong, J., Tawonsawatruk, T., Kamprom, W., Ontong, P., Tanyong, D., Borwornpinyo, S., et al. (2022). Bone marrow-mesenchymal stem cell-derived extracellular vesicles affect proliferation and apoptosis of leukemia cells in vitro. Febs Open Bio, 12 (2), 470–479.

195. Boutin, L., Arnautou, P., Trignol, A., Ségot, A., Farge, T., Desterke, C., et al. (2020). Mesenchymal stromal cells confer chemoresistance to myeloid leukemia blasts through side population functionality and ABC transporter activation. Haematologica, 105 (4), 987–9998.

196. Kouzi, F., Zibara, K., Bourgeais, J., Picou, F., Gallay, N., Brossaud, J., et al. (2020). Disruption of gap junctions attenuates acute myeloid leukemia chemoresistance induced by bone marrow mesenchymal stromal cells. Oncogene, 39 (6), 1198–1212.

197. Hack, T., Bertram, S., Blair, H., Börger, V., Büsche, G., Denson, L., et al. (2020). Exposure of patient-derived mesenchymal stromal cells to TGFB1 supports fibrosis induction in a pediatric acute megakaryoblastic leukemia model. Molecular Cancer Research, 18 (10), 1603–1612.

198. Azadniv, M., Myers, J. R., McMurray, H. R., Guo, N., Rock, P., Coppage, M. L., et al. (2020). Bone marrow mesenchymal stromal cells from acute myelogenous leukemia patients demonstrate adipogenic differentiation propensity with implications for leukemia cell support. Leukemia, 34 (2), 391–403.

199. Mosleh, M., Safaroghli-Azar, A., & Bashash, D. (2020). Pan-HDAC inhibitor panobinostat, as a single agent or in combination with PI3K inhibitor, induces apoptosis in APL cells: An emerging approach to overcome MSC-induced resistance. International Journal of Biochemistry & Cell Biology , 122 , 105734.

200. Schelker, R. C., Iberl, S., Müller, G., Hart, C., Herr, W., & Grassinger, J. (2018). TGF-β1 and CXCL12 modulate proliferation and chemotherapy sensitivity of acute myeloid leukemia cells co-cultured with multipotent mesenchymal stromal cells. Hematology, 23 (6), 337–345.

201. Ruvolo, P. P., Ruvolo, V. R., Burks, J. K., Qiu, Y., Wang, R. Y., Shpall, E. J., et al. (2018). Role of MSC-derived galectin 3 in the AML microenvironment. Biochimica Et Biophysica Acta, 1865 (7), 959–969.

202. Mistry, J. J., Moore, J. A., Kumar, P., Marlein, C. R., Hellmich, C., Pillinger, G., et al. (2021). Daratumumab inhibits acute myeloid leukaemia metabolic capacity by blocking mitochondrial transfer from mesenchymal stromal cells. Haematologica , 106 (2), 589–592.

203. Burt, R. J., Dey, A., Akarca, A., Allen, H., Amerikanou, R., Atkinson, S., et al. (2024). Mitochondrial DsRNA from B-ALL cells stimulates mesenchymal stromal cells to become cancer-associated fibroblasts. Blood Advances, 8 (21), 5696–5709.

204. Karantanou, C., Minciacchi, V. R., Kumar, R., Zanetti, C., Bravo, J., Pereira, R. S., et al. (2023). Impact of mesenchymal stromal cell-derived vesicular cargo on B-cell acute lymphoblastic leukemia progression. Blood Advances, 7 (7), 1190–1203.

205. Chiu, M., Taurino, G., Dander, E., Bardelli, D., Fallati, A., Andreoli, R., et al. (2021). All blasts drive primary mesenchymal stromal cells to increase asparagine availability during asparaginase treatment. Blood Advances, 5 (23), 5164–5178.

206. Zanetti, S. R., Romecin, P. A., Vinyoles, M., Juan, M., Fuster, J. L., Cámos, M., et al. (2020). Bone marrow MSC from pediatric patients with B-ALL highly immunosuppress T-cell responses but do not compromise CD19-CAR T-cell activity. Journal for Immunotherapy of Cancer, 8 (2), Article e001419.

207. Vanegas, N. D. P., Ruiz-Aparicio, P. F., Uribe, G. I., Linares-Ballesteros, A., & Vernot, J. P. (2021). Leukemia-induced cellular senescence and stemness alterations in mesenchymal stem cells are reversible upon withdrawal of B-cell acute lymphoblastic leukemia cells. Int J Mol Sci , 22 (15), 8166.

208. Kihira, K., Chelakkot, V. S., Kainuma, H., Okumura, Y., Tsuboya, N., Okamura, S., et al. (2020). Close interaction with bone marrow mesenchymal stromal cells induces the development of cancer stem cell-like immunophenotype in B cell precursor acute lymphoblastic leukemia cells. International Journal of Hematology, 112 (6), 795–806.

209. Tian, C., Li, Y., Wang, L., Si, J., Zheng, Y., Kang, J., et al. (2022). Blockade of FGF2/FGFR2 partially overcomes bone marrow mesenchymal stromal cells mediated progression of T-cell acute lymphoblastic leukaemia. Cell Death and Disease, 13 (11), Article 922.

210. Yuan, T., Shi, C., Xu, W., Yang, H. L., Xia, B., & Tian, C. (2021). Extracellular vesicles derived from T-cell acute lymphoblastic leukemia inhibit osteogenic differentiation of bone marrow mesenchymal stem cells via miR-34a-5p. Endocrine Journal, 68 (10), 1197–1208.

211. Wang, J., Liu, X., Qiu, Y., Shi, Y., Cai, J., Wang, B., et al. (2018). Cell adhesion-mediated mitochondria transfer contributes to mesenchymal stem cell-induced chemoresistance on T cell acute lymphoblastic leukemia cells. Journal of Hematology & Oncology , 11 (1), 11.

212. Cai, J., Wang, J., Huang, Y., Wu, H., Xia, T., Xiao, J., et al. (2016). ERK/Drp1-dependent mitochondrial fission is involved in the MSC-induced drug resistance of T-cell acute lymphoblastic leukemia cells. Cell Death and Disease, 7 (11), Article e2459.

213. Mallampati, S., Leng, X., Ma, H., Zeng, J., Li, J., Wang, H., et al. (2015). Tyrosine kinase inhibitors induce mesenchymal stem cell-mediated resistance in BCR-ABL + acute lymphoblastic leukemia. Blood, 125 (19), 2968–2973.

214. Jiang, Y. H., Liu, J., Lin, J., Li, S. Q., Xu, Y. M., Min, Q. H., et al. ((2020)). K562 cell-derived exosomes suppress the adhesive function of bone marrow mesenchymal stem cells via delivery of miR-711. Biochemical and Biophysical Research Communications, 521 (3), 584–589.

215. Chai, C., Sui, K., Tang, J., Yu, H., Yang, C., Zhang, H., et al. (2023). BCR-ABL1-driven exosome-miR130b-3p-mediated gap-junction Cx43 MSC intercellular communications imply therapies of leukemic subclonal evolution. Theranostics, 13 (12), 3943–3963.

216. Zuo, S., Sun, L., Wang, Y., Chen, B., Wang, J., Ge, X., et al. (2021). Establishment of a novel mesenchymal stem cell-based regimen for chronic myeloid leukemia differentiation therapy. Cell Death and Disease, 12 (2), Article 208.

217. Petinati, N. A., Petrova, A. N., Chelysheva, E. Y., Shukhov, O. A., Bykova, A. V., Nemchenko, I. S., et al. (2019). Multipotent mesenchymal stromal cells in patients with chronic myeloid leukemia before discontinuation of tyrosine kinase inhibitors. Bulletin of Experimental Biology and Medicine, 167 (4), 580–583.

218. Wan, Z., Chen, X., Gao, X., Dong, Y., Zhao, Y., Wei, M., et al. (2019). Chronic myeloid leukemia-derived exosomes attenuate adipogenesis of adipose derived mesenchymal stem cells via transporting miR-92a-3p. Journal of Cellular Physiology, 234 (11), 21274–21283.

219. Dolinska, M., Cai, H., Månsson, A., Shen, J., Xiao, P., Bouderlique, T. (2023) Characterization of the bone marrow niche in patients with chronic myeloid leukemia identifies CXCL14 as a new therapeutic option. Blood , 142 (1), 73–89.

220. Xu, S., De Veirman, K., De Becker, A., Vanderkerken, K., & Van Riet, I. (2018). Mesenchymal stem cells in multiple myeloma: A therapeutical tool or target? Leukemia, 32 (7), 1500–1514.

221. Rojas-Zambrano, P. M., Meyer-Herrera, J. E., Ruiz-Aparicio, P. F., & Vernot, J. P. (2023). Simultaneously targeting two coupled signalling molecules in the mesenchymal stem cell support efficiently sensitises the multiple myeloma cell line H929 to bortezomib. International Journal of Molecular Sciences, 24 (9), Article 8157.

222. García-Sánchez, D., González-González, A., Alfonso-Fernández, A., Del Dujo-Gutiérrez, M., & Pérez-Campo, F. M. (2023). Communication between bone marrow mesenchymal stem cells and multiple myeloma cells: Impact on disease progression. World Journal of Stem Cells, 15 (5), 421–437.

223. Vafaeizadeh, M., Abroun, S., & Soufi Zomorrod, M. (2024). Effect of human bone marrow mesenchymal stem cell-derived microvesicles on the apoptosis of the multiple myeloma cell line U266. Journal of Cancer Research and Clinical Oncology, 8 (6), 299.

224. Da Ros, F., Kowal, K., Vicinanza, C., Lombardi, E., Agostini, F., Ciancia, R. (2023). IRE1a-induced FilaminA phosphorylation enhances migration of mesenchymal stem cells derived from multiple myeloma patients. Cells, 12 (15):1935.

225. Enukashvily, N. I., Belik, L. A., Semenova, N. Y., Kostroma, I. I., Motyko, E. V., Gritsaev, S. V., et al. (2023). Transcription of WNT genes in hematopoietic niche’s mesenchymal stem cells in multiple myeloma patients with different responses to treatment. Genes, 14 (5), Article 1097.

226. Long, S., Long, S., He, H., Luo, L., Liu, M., & Ding, T. (2023). Exosomal miR-182 derived from bone marrow mesenchymal stem cells drives carfilzomib resistance of multiple myeloma cells by targeting SOX6. Journal of Orthopaedic Surgery and Research, 18 (1), Article 937.

227. Liu, Z. Y., Meng, N. H., Cao, P. P., Jia, Y., Wang, H., Zhang, Y. H., et al. (2023). Bone marrow-derived mesenchymal stem cells inhibit NK cell function via tim-3/galectin-9 in multiple myeloma patients. Clinical and Translational Medicine, 13 (3), Article e1224.

228. Gu, J., Wang, M., Wang, X., Li, J., Liu, H., Lin, Z., et al. (2022). Exosomal miR-483-5p in bone marrow mesenchymal stem cells promotes malignant progression of multiple myeloma by targeting TIMP2. Frontiers in Cell and Developmental Biology, 10 , Article 862524.

229. Liu, Z. Y., Deng, L., Jia, Y., Liu, H., Ding, K., Wang, W., et al. (2022). CD155/TIGIT signalling plays a vital role in the regulation of bone marrow mesenchymal stem cell-induced natural killer-cell exhaustion in multiple myeloma. Clinical and Translational Medicine, 12 (7), Article e861.

230. Garcia-Gomez, A., Li, T., de la Calle-Fabregat, C., Rodríguez-Ubreva, J., Ciudad, L., Català-Moll, F., et al. (2021). Targeting aberrant DNA methylation in mesenchymal stromal cells as a treatment for myeloma bone disease. Nature Communications, 12 (1), Article 421.

231. Liu, Z., Mi, F., Han, M., Tian, M., Deng, L., Meng, N., et al. (2021). Bone marrow-derived mesenchymal stem cells inhibit CD8 + T cell immune responses via PD-1/PD-L1 pathway in multiple myeloma. Clinical and Experimental Immunology, 205 (1), 53–62.

232. Dabbah, M., Lishner, M., Jarchowsky-Dolberg, O., Tartakover-Matalon, S., Brin, Y. S., Pasmanik-Chor, M., et al. (2021). Ribosomal proteins as distinct passengers of microvesicles: New semantics in myeloma and mesenchymal stem cells’ communication. Translational Research, 236 , 117–132.

233. Holthof, L. C., van der Schans, J. J., Katsarou, A., Poels, R., Gelderloos, A. T., Drent, E. (2021). Bone marrow mesenchymal stromal cells can render multiple myeloma cells resistant to cytotoxic machinery of CAR T cells through inhibition of apoptosis. Clin Cancer Res: Off J Am Assoc Cancer Res , 27 (13), 3793–803.

234. Zhao, J., Ma, L., Ni, Z., & Liu, H. (2021). In vitro facilitating role of polygonatum sibiricum polysaccharide in osteogenic differentiation of bone marrow mesenchymal stem cells from patients with multiple myeloma. Biotechnology Letters, 43 (7), 1311–1322.

235. Liu, Z., Liu, H., He, J., Lin, P., Tong, Q., & Yang, J. (2020). Myeloma cells shift osteoblastogenesis to adipogenesis by inhibiting the ubiquitin ligase MURF1 in mesenchymal stem cells. Science Signaling, 13 (633), Article eaay8203.

236. Zhang, G., Miao, F., Xu, J., & Wang, R. (2020). Mesenchymal stem cells from bone marrow regulate invasion and drug resistance of multiple myeloma cells by secreting chemokine CXCL13. Bosnian Journal of Basic Medical Sciences / Udruženje Basičnih Mediciniskih Znanosti = Association of Basic Medical Sciences, 20 (2), 209–217.

237. Su, C., Tao, D., Ren, L., Guo, S., Zhou, W., Wu, H., et al. (2020). The effective role of sodium copper chlorophyllin on the dysfunction of bone marrow mesenchymal stem cells in multiple myeloma via regulating TGF-β1. Tissue And Cell, 67 , Article 101406.

238. Jin, J., Cheng, S., Wang, Y., Wang, T., Zeng, D., Li, Z., et al. (2019). SRC3 expressed in bone marrow mesenchymal stem cells promotes the development of multiple myeloma. Acta Biochimica Et Biophysica Sinica, 51 (12), 1258–1266.

239. Fernando, R. C., Mazzotti, D. R., Azevedo, H., Sandes, A. F., Rizzatti, E. G., de Oliveira, M. B., et al. (2019). Transcriptome analysis of mesenchymal stem cells from multiple myeloma patients reveals downregulation of genes involved in cell cycle progression, immune response, and bone metabolism. Scientific Reports, 9 (1), Article 1056.

240. Yang, H., Zheng, Y., Zhang, Y., Cao, Z., & Jiang, Y. (2017). Mesenchymal stem cells derived from multiple myeloma patients protect against chemotherapy through autophagy-dependent activation of NF-κB signaling. Leukemia Research, 60 , 82–88.

241. Cippitelli, M., Stabile, H., Kosta, A., Petillo, S., Lucantonio, L., Gismondi, A., et al. (2023). Role of NF-κB signaling in the interplay between multiple myeloma and mesenchymal stromal cells. International Journal of Molecular Sciences, 24 (3), Article 1823.

242. Zhao, P., Chen, Y., Yue, Z., Yuan, Y., & Wang, X. (2017). Bone marrow mesenchymal stem cells regulate stemness of multiple myeloma cell lines via BTK signaling pathway. Leukemia Research, 57 , 20–26.

243. Dabbah, M., Attar-Schneider, O., Tartakover Matalon, S., Shefler, I., Jarchwsky Dolberg, O., Lishner, M. Microvesicles derived from normal and multiple myeloma bone marrow mesenchymal stem cells differentially modulate myeloma cells’ phenotype and translation initiation. Carcinogenesis , 38 (7), 708–16.

244. Li, J., Wu, Z., Zhao, L., Liu, Y., Su, Y., Gong, X., et al. (2023). The heterogeneity of mesenchymal stem cells: An important issue to be addressed in cell therapy. Stem Cell Research & Therapy , 14 (1), 381.

245. Li, R., Tu, J., Zhao, J., Pan, H., Fang, L., & Shi, J. (2021). Mesenchymal stromal cells as prophylaxis for graft-versus-host disease in haplo-identical hematopoietic stem cell transplantation recipients with severe aplastic anemia?-a systematic review and meta-analysis. Stem Cell Research & Therapy , 12 (1), 106.

246. Wu, X., Darlington, D. N., Christy, B. A., Liu, B., Keesee, J. D., Salgado, C. L., et al. (2022). Intravenous administration of mesenchymal stromal cells leads to a dose-dependent coagulopathy and is unable to attenuate acute traumatic coagulopathy in rats. The Journal of Trauma and Acute Care Surgery, 92 (3), 542–552.

247. Lechanteur, C., Briquet, A., Bettonville, V., Baudoux, E., & Beguin, Y. (2021). MSC manufacturing for academic clinical trials: From a clinical-grade to a full GMP-compliant process. Cells, 10 (6), Article 1320.

248. Gong, X., Sun, D., Li, Z., Shi, Q., Li, D., & Ju, X. (2020). Three-dimensional culture of umbilical cord mesenchymal stem cells effectively promotes platelet recovery in immune thrombocytopenia. Biol Pharm Bull, 43(7), 1052–60.

249. Quiroz-Reyes, A. G., González-Villarreal, C. A., Martínez-Rodriguez, H., Said-Fernández, S., Salinas-Carmona, M. C., & Limón-Flores, A. Y. (2022). A combined antitumor strategy of separately transduced mesenchymal stem cells with soluble TRAIL and IFNβ produces a synergistic activity in the reduction of lymphoma and mice survival enlargement. Molecular Medicine Reports, 25 (6), Article 206.

250. Quiroz-Reyes, A. G., Gonzalez-Villarreal, C. A., Limon-Flores, A. Y., Delgado-Gonzalez, P., Martinez-Rodriguez, H. G., Said-Fernandez, S. L., et al. (2023). Mesenchymal stem cells genetically modified by lentivirus-express soluble TRAIL and interleukin-12 inhibit growth and reduced metastasis-relate changes in lymphoma mice model. Biomedicines, 11 (2), Article 595.

251. Zhang, J., Zhong, M., Zhong, W., Lan, Y., Yuan, Z., Duan, Y., et al. (2022). Construction of tandem Diabody (IL-6/CD20)-secreting human umbilical cord mesenchymal stem cells and its experimental treatment on diffuse large B cell lymphoma. Stem Cell Research & Therapy , 14 (1), 473.

252. Wang, X., Cabrera, F. G., Sharp, K. L., Spencer, D. M., Foster, A. E., & Bayle, J. H. (2021). Engineering tolerance toward allogeneic CAR-T cells by regulation of MHC surface expression with human herpes Virus-8 proteins. Molecular Therapy, 29 (2), 718–733.

253. Fallati, A., Di Marzo, N., D’Amico, G., & Dander, E. (2022). Mesenchymal stromal cells (MSCs): an ally of B-cell acute lymphoblastic leukemia (B-ALL) cells in disease maintenance and progression within the bone marrow hematopoietic niche. Cancers , 14 (14), 3303.

254. Batsali, A. K., Georgopoulou, A., Mavroudi, I., Matheakakis, A., Pontikoglou, C. G., & Papadaki, H. A. (2020). The role of bone marrow mesenchymal stem cell derived extracellular vesicles (MSC-EVs) in normal and abnormal hematopoiesis and their therapeutic potential. Journal of Clinical Medicine, 9 (3), Article 856.

255. Boregowda, S. V., & Phinney, D. G. (2016). Quantifiable metrics for predicting MSC therapeutic efficacy. Journal of Stem Cell Research & Therapy, 6 (11), Article 365.

256. Van Grouw, A., Colonna, M. B., Maughon, T. S., Shen, X., Larey, A. M., Moore, S. G., et al. (2023). Development of a robust consensus modeling approach for identifying cellular and media metabolites predictive of mesenchymal stromal cell potency. Stem Cells, 41 (8), 792–808.

257. Jin, H. J., Bae, Y. K., Kim, M., Kwon, S. J., Jeon, H. B., Choi, S. J. (2013). Comparative analysis of human mesenchymal stem cells from bone marrow, adipose tissue, and umbilical cord blood as sources of cell therapy. Int J Mol Sci, 14(9), 17986–18001.

258. Hong, Z., Zhao, Y., Pahlavan, S., Wang, X., Han, S., Wang, X., et al. (2025). iPSC modification strategies to induce immune tolerance. Life Medicine, 4 (3), Article lnaf016.

259. Zhang, J., Chen, M., Liao, J., Chang, C., Liu, Y., Padhiar, A. A., et al. (2021). Induced pluripotent stem cell-derived mesenchymal stem cells hold lower heterogeneity and great promise in biological research and clinical applications. Frontiers in Cell and Developmental Biology, 9 , Article 716907.

260. Movahed, A. Y., Bagheri, R., Savatier, P., Šarić, T., & Moradi, S. Elimination of tumorigenic pluripotent stem cells from their differentiated cell therapy products: An important step toward ensuring safe cell therapy. Stem Cell Reports , 20 (7), 102543.

261. Lezmi, E., & Benvenisty, N. (2022). The tumorigenic potential of human pluripotent stem cells. Stem Cells Translational Medicine, 11 (8), 791–796.

Associated Data

Data Availability Statement

No datasets were generated or analysed during the current study.

Not applicable.