Review: progression and heterogeneity of multiple sources of mesenchymal stromal cells for the treatment of rheumatoid arthritis.

Introduction

Rheumatoid arthritis (RA) is a chronic autoimmune disease that affects the joints of approximately 0.5-1% of adults worldwide, resulting in joint damage, persistent synovial hyperplasia [ 1 , 2 ].Estimates of the incidence or prevalence of various autoimmune disease groups in Chinese adults were determined from 566,000 studies from1995, with autoimmune thyroid disease, Graves’ disease, and RA being the top three [ 3 ]. Recent studies have identified 31.5–35.5 million adults in China (2.7-3.0% of the Chinese population) with autoimmune diseases, roughly the same as Western estimates [ 4 , 5 ], Most of this burden comes from RA. It is noteworthy that life expectancy in RA is gradually increasing [ 6 ], although the incidence of RA is increasing every year, and the joint pain and swelling and joint deformities caused by the disease severely diminish the quality of life of patients and place a heavy burden on the global healthcare system. This trend is attributed to the fact that current RA treatments focus on symptomatic relief, functional maintenance and slowing down tissue damage [ 7 ].However, the increase in RA is not uniform across all regions, and there are marked differences in prevalence between regions. For example, developed countries and urban settings have a higher prevalence than developing countries and rural settings. The burden of autoimmune disease in China is generally lower than in the rest of the global human population, but as many as 3 out of every 100 Chinese adults (> 31 million people) suffer from autoimmune disease, posing a health concern for the Chinese population [ 3 ].

At the molecular level, the pathogenesis of RA is an immune imbalance leading to synovial inflammation and joint destruction, with the combination of aberrant activation of T lymphocyte cells(T cells)and B lymphocyte cells (B cells), massive release of inflammatory factors, and aberrant function of synovial fibroblasts [ 8 ].These inflammatory responses further promote the destruction of articular cartilage and bone through the interaction of immune cells with fibroblasts. Conventional treatments are difficult to achieve the synergistic regulation of immune homeostasis reconstruction and tissue repair, and an early break in this cycle is the key to treatment. The main emphasis in the pathogenesis of RA is on the dysfunction of T cells and cells B cells the immune microenvironment. Understanding the mechanisms has led to the emergence of compliant drugs, such as rituximab, which reduces autoantibody levels by targeting CD20 [ 9 ], The mechanism of action needs to be further studied. The pathogenesis and influencing factors of RA are shown in Fig. 1 .

Several challenges persist in contemporary in RA, leading to the exploration of novel therapeutic options that may address these gaps. Recent guidelines for the management of RA recommend starting to de-treat methotrexate (MTX) as a single agent in all moderately to severely active disease [ 10 , 11 ], However, there are still clinical cases where MTX monotherapy alone fails to relieve the disease [ 12 ]. Janus kinase (JAK) inhibitors are among the more popular biologics recently used to treat RA, and their effectiveness depends on the role of JAK and signal transducer and activator of transcription constituents in cytokine signaling in RA [ 13 ]. However, JAK inhibitors are relatively new drugs and their long-term safety has not been fully clarified. A study suggests an increased risk of venous thromboembolism with the use of JAK inhibitors in immune-mediated inflammatory diseases [ 14 ]. Neither biologics nor Disease-Modifying Anti-Rheumatic Drugs (DMARDS) can reverse tissue damage, and one of the promising avenues to address the existing challenges in the clinical practice of RA disease is regenerative medicine. Indeed, in the last decade, extensive research has been conducted for the implementation of cell therapy with Mesenchymal stromal cells(MSCs) [ 15 ]. MSCs provide a breakthrough strategy for RA treatment through a bi-directional immune-repair mechanism, but the challenge of heterogeneity of efficacy needs to be resolved through technological innovation and interdisciplinary collaboration to ultimately make the leap from basic research to clinical application. In this paper, we analyze the regulatory mechanisms of MSCs from different sources and their heterogeneity with advances in engineering modifications.

This review is based on an extensive survey of the original English literature on the mechanisms, heterogeneity and efficacy of MSCs in the treatment of RA. Various combinations of the terms “MSCs”, “RA”, “efficacy”, “cell therapy”, “immunomodulation”, “safety”, “clinical trials’”and “clinical studies”were used. An internet search was also conducted on ClinicalTrials.gov, the global clinical trials registry, using the terms “RA”, “MSCs”, “clinical trial”, “clinical study”, “safety”, “safety”, “clinical trial” and “clinical study” in various combinations. “MSCs” and other search terms were also used. Most of the included literature was published within the last 5 years, with literature published within the last 10 years excluded due to scarcity. Additionally, non-English articles, conference abstracts, and older articles were excluded to ensure currency.

Application of cell therapy in RA: from CAR-T to MSCs therapy

Cell therapy represents a medical technology that employs live cells for the treatment of diseases and the modulation of impaired tissues or functions in the human body. In autoimmune disorders like RA, it has the potential to augment or rejuvenate the patient’s immune system. A range of cell therapies, encompassing immunotherapy, gene therapy, platelet-rich plasma therapy, and MSCs therapy, are utilized across diverse medical domains [ 16 ].Before the emergence of MSCs therapy in the field of RA, an important breakthrough was the development of Chimeric Antigen Receptor T-Cell Immunotherapy(CAR-T) [ 17 ]. CAR-T therapies were first proposed in the late 1980s by Israeli scientists Zelig Eshhar, who showed that expression of an antibody recognition structural domain in T cells can specifically redirect cytotoxic activity, independent of T cells receptor or human leukocyte antigen expression [ 18 , 19 ]. CAR-T therapy is currently approved as a therapeutic approach for diseases such as refractory leukemia, lymphoma and multiple myeloma, as well as a promising treatment for a range of systemic autoimmune diseases. Despite the encouraging discoveries in the early stages, it took two decades of development to improve safety and efficacy and slowly step into the limelight. These innovative therapeutic approaches hold great promise, and many are currently progressing through preclinical development and clinical trials. It is conceivable that some of these strategies could eventually be optimized for use in the treatment of RA disease. In recent years, MSCs have shown strong potential for RA therapy due to their class of unique biological properties, particularly in terms of immunomodulatory mechanisms. MSCs have the capacity for self-renewal and differentiation, and are usually cultured in vivo, allowing clinicians and researchers to direct cell lineage progression according to the details of the tissue in need of repair [ 20 ]. Depending on their origin, they can differentiate into a variety of cell lines, including bone, adipose, and cartilage, ensuring a continuous source of living cells due to their strong self-renewal capacity, and a power source for MSC’s powerful tissue repair and regeneration strategies [ 21 , 22 ]. Table 1 introduces the application scope of MSCs from different sources in laboratory research and animal models, revealing the powerful role of MSCs. In addition to the tissue repair and regenerative capacity, the powerful immunomodulatory properties of MSCs are of greater interest. MSCs exerts a potent immunomodulatory effect by inhibiting pro-inflammatory immune cells and promoting regulatory T cells (Tregs) expansion, thereby reducing the inflammatory process, while inhibiting B cells proliferation and differentiation as well as immunoglobulin production, contributing to the polarization of macrophages into an anti-inflammatory phenotype, inhibiting neutrophil recruitment and preventing the maturation of dendritic cells(DCs) maturation, thereby improving the inflammatory microenvironment in RA patients [ 23 ]. Experimental data on MSCs-based RA treatment is increasing, however, the clinical side is yet to be carried out on a large scale, but there are teams revealing clinical data showing promising results. For example, Ridhima Vij et al. conducted a phase I/IIa non-randomized open-label study to evaluate the safety and efficacy of a single intravenous infusion of autologous adipose-derived mesenchymal stromal cells (AD-MSCs) over 52 weeks in patients with active RA [ 24 ]. Studies have shown that a single intravenous injection of AD-MSCs is safe and effective in improving joint function in patients with active RA, but larger randomized placebo-controlled trials are needed to confirm the results.

The immune regulatory mechanism of MSCs regulating RA

MSCs can be extracted and isolated from different tissues, and it from these sources have different properties, differentiation potentials and application prospects. In the past decade, scholars at home and abroad have accumulated many research results around the safety and preliminary efficacy of MSCs, mainly focusing on the balance of T cell subpopulations and the regulation of macrophage polarization to achieve immune reconstruction of RA through the synergistic effect of multiple pathways [ 35 – 37 ], MSCs can also inhibit the maturation and function of DCs by secreting molecules such as Prostaglandin E2(PGE2) and Interleukin 10(IL-10), thereby suppressing immune responses [ 23 ].This capability empowers MSCs to effectively intervene in overactivated or disrupted immune responses, exerting a dynamic and regulatable role in maintaining immune homeostasis, thereby offering fresh perspectives for the treatment of RA or other autoimmune disorders. This section meticulously outlines the mechanisms underlying MSCs therapy for RA, encompassing the balance of T cells subpopulations and the induction of macrophage polarization. The immune regulatory mechanism of MSCs in treating RA is shown in Fig. 2 .

T cell subpopulation balance

One of the core pathological features of RA is the imbalance of immune homeostasis mediated by T cells. but some evidence suggests a role for T helper cell(Th)subsets, Tregs and their cytokines in the pathogenesis of RA [ 38 , 39 ]. Such as the imbalance between Treg/Th17 and Th1/Th2 cells affects the development of RA. In the synovial microenvironment of RA, the abnormal activation and proliferation of pro-inflammatory Th(Th1 and Th17) contribute to the persistent development of inflammation, Meanwhile, the decrease in the number or impairment of the function of Tregs, which possess immunosuppressive capabilities, further exacerbates the breakdown of immune tolerance [ 40 ]. Niu et al. conducted an analysis of Th17/Treg at various levels, encompassing cell frequency and the secretion of associated cytokines, The findings revealed that the equilibrium of peripheral Th17/Treg was disturbed in RA patients, suggesting that the imbalance of Th17/Treg might synergistically interact with micro-inflammation to influence the progression of RA [ 41 ]. Although the immune mechanism of MSCs is not fully understood, research suggests that cell contact seems to play a role in it [ 42 ]. During the progress of RA, long-term high levels of inflammatory cytokines stimulate MSCs to produce various cytokines, such as hepatocyte growth factor (HGF) and transforming growth factor-β (TGF-β), soluble factors like PGE2, indoleamine2,3-dioxygenase (IDO), and nitric oxide (NO). These mediators can inhibit effector T cells, maximizing their immunomodulatory effects [ 43 – 45 ].

The regulatory role of macrophage phenotype transformation

In addition to the dysregulation of immune cell homeostasis, an important point is the macrophage phenotypic switch. Macrophages are essential intrinsic immune cells that function as primary phagocytes in multicellular organisms and play a crucial role in natural immunity. They perform a variety of functions including pathogen clearance, chemotaxis, immunomodulation and maintenance of tissue homeostasis [ 46 , 47 ]. An imbalance between pro-inflammatory macrophages (M1) and anti-inflammatory macrophages (M2) in synovial tissue leads to a range of inflammatory production [ 48 ]. In general, M1 macrophages secrete pro-inflammatory molecules, including tumor necrosis factor-α (TNF-α) and Interleukin-1β (IL-1β), whereas M2 macrophages secrete immunomodulatory factors such as IL-10 [ 49 ]. MSCs mainly regulate macrophage function through intercellular mechanisms and the release of soluble factors, releasing IL-10, TGF-β, PGE2, etc., activating the STAT6/PPAR γ signaling pathway in macrophages, and driving M2 phenotype differentiation [ 50 ]. At the same time, MSCs secrete PGE2, inducing M1 macrophages to transition to M2 macrophages, thereby balancing the inflammatory response [ 51 ]. Available data suggest a strong link between the anti-inflammatory effects of EV and macrophage polarization. It has been shown that macrophages are the most abundant immune cells in the synovium and are strongly associated with synovial inflammation and OA severity [ 52 ], In OA mice, IL-6-EV enhances mt-ND3 expression in synovial macrophages in vivo and promotes M2 macrophage polarization, thereby reducing the severity of OA synovitis [ 53 ].

Mechanism and application of extracellular vesicles from mesenchymal stromal cells

Exosomes, a subclass of Extracellular Vesicles ( EVs) secreted by MSCs, EVs with a diameter of 50–150 nanometers are commonly referred to as exosomes [ 54 ].Compared to cell therapy, the use of Exosomes may have some advantages [ 55 ].Mesenchymal Stromal Cell-Derived Exosomes (MSC-Exos) transport complex proteins, nucleic acids, and contain abundant molecules such as miRNA and anti-inflammatory cytokines [ 56 ]. Some miRNAs exhibit anti-inflammatory properties, such as miR-24-3p, miR-27b, miR-1466, miR-147, miR-182, miR-6873, and miR-7704 [ 57 – 63 ]. In addition to anti-inflammatory properties, MSC-Exos also produce repair factors including growth factors and cytokines such as TGF-β, vascular endothelial growth factor, β-fibroblast growth factor, as well as anti-inflammatory cytokines IL-10, PGE2 [ 64 – 66 ]. Other studies have found that active molecules carried by MSC-Exos, such as TGF - β, recombinant indole2,3-dioxygenase, and miR-125a-3p, enable MSC-Exos to inhibit T cell proliferation and activation [ 67 ].Ye et al. injected Bone Marrow Stromal Cells-derived Exosomes(BMSC- Exos) into RA mice, and the results showed that BMSC -Exos reduced the proportion of differentiated Th17 cells while increasing the proportion of Treg cells, which to some extent balanced Th17 cells and Treg cells to alleviate the damage caused by RA [ 68 ].The study by Wei et al. also demonstrated the protective effect of MSC-Exos on cartilage degradation in collagen induced arthritis (CIA) mouse models. The research showed that MSC-Exos can inhibit inflammation induced degradation of cartilage matrix by regulating immune cell inflammatory factors, thereby reducing soft bone damage. It also indicated that MSC-Exos is a promising and effective treatment method for early RA [ 69 ].

Stromal cell-driven mechanisms of tissue repair

Patients with inflammatory arthritis frequently present with cartilage and osteosclerotic damage, and cartilage defects are detected in approximately 60% of all arthroscopic procedures [ 70 , 71 ].Repair of damaged tissue is therefore an unmet clinical need in rheumatology. Regenerative medicine is gradually coming into the limelight with the aim of repairing damaged tissues without scarring and restoring structure and function, involving two main strategies. One is through tissue engineering, combining cells or materials to exert tissue repair. The study by Gan et al. demonstrated the clinical value of anchored MSCs membranes onto drug-loaded polymeric cores as biomimetic nanomedicines for the treatment of RA and related disorders by means of engineered materials, whereby constructed nanoparticles enhanced accumulation in inflamed joints to achieve affinity for activated macrophages and synovial fibroblasts and showed better efficacy in CIA mice [ 72 ].Similarly Ma et al.‘s study developed a biomimetic liposome based on MSCs, which improves the efficiency of drug targeting to diseased patients and also provides a new perspective on targeted drug delivery therapies for inflammatory diseases [ 73 ].The second is to activate intrinsic repair mechanisms by targeting genetic pathways associated with endogenous stromal cells [ 74 ].

Synovial homeostasis reconstruction and cartilage repair

The core mechanism of MSCs therapy for RA lies in the reconstruction of synovial tissue to achieve dynamic homeostasis, a process that involves systematic regulation of the immune microenvironment, cellular phenotype and metabolic network. Imbalance of synovial homeostasis is the core pathological feature of RA, which is manifested by abnormal activation of fibroblasts-like synoviocytes (FLS), infiltration of immune cells and progressive destruction of extracellular matrix (ECM).Conventional treatments can only control the inflammatory response to a certain extent, but often do nothing about the synovial lesions and joint damage that have already occurred. A study has shown that Berbamine, a natural compound extracted from traditional Chinese medicine (TCM), has an inhibitory effect on FLS and alleviates RA by promoting reactive oxygen species production and DNA damage in FLS in RA which provides a new idea for the clinical treatment of RA in TCM [ 75 ].Similarly MSCs, with their unique regenerative and repair capabilities, offer new ideas for the treatment of RA. In terms of immunomodulation, they can inhibit the differentiation of pro-inflammatory Th17 cells, while promoting the proliferation of Tregs and reshaping the immune balance. Wang et al. demonstrated that exosomes of UC-MSCs carrying miRNA-150-5p efficiently activated the immunosuppressive function of T cells [ 76 ].In the case of diseased synovial fibroblasts, it is possible to inhibit their abnormal proliferative and migratory properties and to reduce the secretion of matrix metalloproteinases, thus blocking the process of synovial tissue erosion of cartilage.

The differences in the heterogeneity, efficacy and safety of the various sources of MSCs

MSCs as a promising therapeutic tool in regenerative medicine and immune-related disease treatment, particularly for conditions like RA, owing to their biological properties. These cells exhibit a capacity for self-renewal, allowing them to proliferate extensively in culture while maintaining their undifferentiated state, which is crucial for generating sufficient cell numbers for clinical applications. Beyond their replicative potential, MSCs possess the remarkable ability to differentiate into multiple cell lineages, including osteoblasts, chondrocytes, adipocytes, making them valuable for tissue repair and regeneration [ 77 ].However, the biological characteristics and therapeutic efficacy of MSCs vary significantly depending on their tissue sources. Currently, clinical research primarily focuses on UC-MSCs, AD-MSCs, and BM-MSCs [ 78 ]. While MSCs derived from these sources show no significant differences in morphology and immunophenotype, they differ in proliferation ability, differentiation potential, and clinical feasibility, each with its own advantages and limitations. Although studies have shown significant advances in the effectiveness of MSCs in treating RA. the inherent heterogeneity of MSCs cannot be overlooked. This heterogeneity may be closely linked to factors such as donor age, donor health status, and the diverse microenvironments associated with MSCs. A deep understanding of these variations is crucial for refining the clinical selection of MSCs [ 77 , 79 ].

Bone marrow(BM)was the first reported source of MSCs, and research has focused on the potential of BM-MSCs in treating RA, Since their initial discovery in the bone marrow stroma by Friedenstein and colleagues in the 1970s, BM-MSCs have become a cornerstone of regenerative and immunomodulatory therapy research [ 80 ].In Table 2 we present information on the efficacy, sample size, clinical stage and other safety aspects of MSCs from different sources. As a continuation, more detailed content can be found in Table 3 . Proliferative capacity is a key factor that influences the in vitro amplification and clinical applicability of MSCs, However BM harvesting is a highly invasive, and the number of MSCs, their differentiation potential, and maximum lifespan decline with donor age [ 81 , 82 ]. A study on refractory RA patients treated with intravenous infusions of 1 × 10⁶ BM-MSCs per kilogram of body weight showed that while BM-MSCs improved disease severity without adverse events, the percentage of Tregs decreased from 1 to 12 months after the injection. This may require multiple injections or higher doses of BM-MSCs to maintain [ 83 , 84 ]. The potential of BM-MSCs was further supported by a study from Ahmadreza Jamshidi et al., where six refractory RA patients exhibited varying degrees of disease remission [ 83 , 85 ]. Previous studies have demonstrated the use of allogeneic MSCs as a treatment for RA instead of autologous MSCs [ 86 ], Notably, allogeneic BM-MSCs were associated with a significant reduction in the Th17 cell ratio in systemic lupus erythematosus [ 87 ], However, more clinical trials are needed to confirm the efficacy of allogeneic MSCs in RA. An alternative approach is cell-free therapy using EVs derived from BM-MSCs, which offers minimal immunogenicity and avoids allograft rejection risks [ 88 ]. Nevertheless, BM-MSCs tend to undergo chondrocyte hypertrophy and bone formation, potentially making them less suitable for articular cartilage repair [ 89 , 90 ].UC-MSCs, owing to their fetal origin and higher telomerase activity, exhibit greater proliferative potential and lower immunogenicity than BM-MSCs. Moreover, they can be obtained through less invasive methods that pose no harm to the mother or infant [ 91 , 92 ].In the study by Eun Hye Park et al., different doses of UCB-MSCs injections were used. The results showed that the higher dose of UCB-MSCs had a higher potential without causing any adverse events. UCB-MSCs also exhibited immunomodulatory properties, enabling allogeneic transplantation. Furthermore, it demonstrated a faster rate of osteogenesis compared to BM-MSCs, potentially due to a higher initial isolation frequency of bone progenitors from UCB-MSCs compared to BM-MSC [ 93 ], Suitable for adult cartilage repair [ 94 ].A recent phase I/IIa trial in which participants received a single intravenous infusion of 2 × 10⁸ autologous AD-MSCs from generation 4 showed that various markers improved following treatment, However, a few adverse events occurred [ 24 ]. In another trial, intravenous infusion of allogeneic AD-MSCs also resulted in adverse events, with infections being common. However, it was not established whether these were related to the injection of the AD-MSCs [ 95 ]. It is also worth noting that, similarly to autologous BM-MSCs, the cells tended to wane or fluctuate after three months of administration, and both require repeated injections to maintain efficacy. The infusion of AD-MSCs in patients with osteoarthritis of the knee has also been shown to be effective, However, studies have shown that AD- MSCs have less of an effect on quality in terms of patient age or morbidity [ 96 , 97 ], It can reduce hypertrophy and dedifferentiation of chondrocytes, inhibit synovial thickening, and prevent joint destruction. This makes it a powerful treatment for osteoarthritis [ 98 – 100 ].Shiratsuki et al. compared the use of AD-MSCs and BM-MSCs in the treatment of cirrhosis. They found that increasing doses of AD-MSCs decreased survival in mice, primarily due to pulmonary thrombosis. However, no dose-dependency was observed for BM-MSCs [ 101 ].Similarly, Zhou et al. demonstrated that the therapeutic effect of AD-MSCs is more stable than that of BM-MSCs [ 102 ], This may be because AD-MSCs are better adapted to survive in hypoxic joint cavities and are more effective at modulating inflammation.

We outline the efficacy and safety of cells from three different sources, as well as their heterogeneity. The heterogeneity of MSCs is inherent and influenced by various factors, including donor age, health status, generation and source. Before being infused into the body, MSCs is prepared under Good Manufacturing Practice conditions. It is then tested for cell viability and purity (CD31, CD34 and CD45), as well as identity (CD73 and CD90). Sterility testing is also performed to check for bacterial and fungal contamination, as well as endotoxin and mycoplasma contamination. This ensures cell purity and reduces heterogeneity [ 103 ].MSCs are susceptible to microenvironmental factors that can result in reduced cell differentiation capacity and low survival rates [ 104 ].Heterogeneity can also be reduced in the clinic by optimizing the preparation or in vitro expansion process. For example, culturing in a low-oxygen environment (3% O₂) can help to maintain stromal cell properties and reduce cellular senescence and ageing [ 105 ]、Use a serum-free medium or heterogeneous serum for faster proliferation rates [ 106 , 107 ]、Three-dimensional culture conditions, such as hydrogels and microporous scaffolds, promote cell proliferation and migration [ 104 ]、Vitrification cryopreservation techniques improve cell viability [ 108 ].The main reason for the controversy surrounding the choice between autologous and allogeneic cells is that the latter are stored in cell banks and readily available to patients. In contrast, autologous cell therapy is more complex. Not only does it require a cumbersome extraction process, but it also requires a much longer period of in vitro expansion to obtain enough cells. Although different sources of MSCs have shown better efficacy, it has been observed that this wanes over time and that multiple repeated injections may be required for maintenance. Current evidence suggests that more pronounced therapeutic effects may be achieved at higher MSCs doses; however, this requires verification through rigorous long-term monitoring and follow-up studies. The preparation of MSCs involves complex, multi-step processes that currently lack internationally standardized protocols. This methodological heterogeneity not only precludes direct comparison between studies but also introduces substantial variability in clinical outcomes. To address these challenges, establishing standardized protocols for MSCs preparation must be prioritized. Future research efforts should focus on developing a comprehensive quality control framework that harmonizes critical parameters including cell source selection, culture conditions, characterization methods, and quality assessment criteria. In terms of the safety of MSCs infusion, the Japanese Society for Regenerative Medicine has set up a working group and formulated recommendations for physicians on management standards for regenerative medicine involving intravenous administration of MSCs [ 109 ].Thrombotic events are the main adverse effect of MSCs vascular injections. Intravenous infusion of MSCs increases the likelihood that they will become trapped in capillaries during circulation. This increases the risk of embolic events, particularly in the lungs, which have a high capillary density [ 109 ].Although no major adverse events occurred in the previous trial, some patients reported temporary joint pain, swelling and restricted movement [ 24 , 83 , 84 ].Several issues still need to be addressed before MSCs can be widely used. Current clinical trials investigating MSCs therapy for RA involve only a limited number of patients, resulting in insufficient statistical power for robust efficacy and safety assessments. Future studies should incorporate larger cohorts to enable more reliable clinical evaluations. Moreover, the observation periods in existing trials are relatively brief (typically ≤ 6 months), while longer-term follow-up may be required to fully assess therapeutic outcomes and potential adverse effects. Another limitation of current research is the predominant comparison of either autologous or allogeneic MSCs against placebo controls. Direct comparative studies between autologous and allogeneic MSCs therapies would provide valuable insights for determining the optimal treatment strategy.

Engineering strategies and challenges

MSCs have applications in RA disease due to their immunomodulatory properties and tissue repair potential. However, natural MSCs suffer from low homing efficiency, short survival time and unstable efficacy [ 114 ]. In recent years, optimization of MSCs through strategies such as gene editing, biomaterial-assisted delivery and engineering of EVs has significantly improved their therapeutic efficacy. Studies have shown a close correlation between gene polymorphisms and autoimmune diseases, and in the meantime, gene editing technology has gradually attracted attention. It has also been demonstrated that clustered regularly interspaced short palindromic Repeats-CRISPR associated protein 9(CRISPR-Cas9) can be used to mitigate autoimmune diseases by knocking down the proprotein convertase subtilisin/kexin type 9 (PCSK9) or blocking PCSK9 [ 115 ]. Chen et al. similarly developed a FLS membrane protein fused with liposomes biomimetic nanoparticles, an innovative approach to utilize FLS membrane protein-mediated homologous targeting to direct liposomes to inflamed joints and promote the release of cargo from synovial cells [ 116 ]. shin et al. also proposed an MSCs mimetic nano-encapsulation technology, which improves the advantages in targeted drug delivery, where drug molecules can be preferentially delivered to synovial inflammatory regions in a sustained or controlled manner [ 117 , 118 ].However, the study is still in the early research stage and more attention should be paid to nanotoxicity. In addition to increasing the homing effect of MSCs in terms of targeting, Shi et al. encapsulated bone-derived MSCs in alginate hydrogels, which can improve cell survival and retention in situ and maximize in vivo efficacy [ 119 ]. In addition, the application of 3D printing technology in cartilage repair is gradually changing the treatment mode of cartilage injury in traditional medicine. Currently it has been applied to the application of articular cartilage defects, etc. Zhao et al.‘s study designed a porous metal scaffold and infliximab-based hydrogel through 3d printing technology, and the study proved that this composite scaffold supported the proliferation, differentiation, and ECM production of ADMSCs in vitro, which could significantly improve the repair of damaged cartilage [ 120 ]. Despite these encouraging preliminary results, the use of MSCs to treat RA is still in the clinical trial stage and some way from becoming a standard treatment. The process of clinical translation faces several challenges, including regulatory uncertainty, difficulties in standardizing manufacturing processes and clinical translation, and costs. Traditional drug review requires clear targets, a stable chemical structure and reproducible efficacy. However, these criteria are too rigid for multi-target, multi-mechanism MSCs therapies. The lack of uniform standards may lead to inconsistent therapeutic efficacy and safety, as well as greater regulatory difficulties. Furthermore, as live cell products, MSCs require complex extraction and culture processes, which makes it challenging to achieve consistency between batches and increase production. Small differences in the preparation process can result in significant variations in cell safety and efficacy. Long-term culture during expansion can lead to cell senescence or genetic mutation, affecting efficacy and safety. There are also differences between cells from different sources, which limits the scalability of MSCs. Clinical translation also has cost implications that cannot be ignored. Preliminary research and development, as well as cell extraction and culture processes, are costly. Long-term follow-up is also required to monitor the efficacy and safety of MSCs after treatment, making the clinical translation process challenging. The clinical translation of MSCs is a very arduous task involving many obstacles, and overcoming these requires longer-term clinical trials and cooperation in various areas.

Conclusion

Current research suggests that MSCs hold promise for effective RA treatment. As the disease continues to be explored, the advent of biologics, from traditional Nonsteroidal Anti-inflammatory Drugs (NSAIDs), and hormonal and DMARDs to a variety of biologics, has contributed significantly to the development of the disease. The emergence of cellular therapies for patients who are poorly responsive or refractory is also promising, as they can modulate aberrant immune responses more precisely than conventional drugs, rather than simply suppressing overall immune function. In terms of long-term efficacy, some cell therapies have shown promise for achieving durable disease remission and may even reduce patients’ dependence on conventional medications. MSCs, which are the focus of this paper, have received extensive attention and research in recent years due to their dual mechanisms of immune regulation and tissue repair. By secreting anti-inflammatory factors to inhibit pro-inflammatory cells while Tregs can restore immune balance and reduce joint autoimmune attacks, MSCs are more inclined to local regulation and reduce the risk of infection than traditional DMARDs or JAK inhibitors. Furthermore, as various MSCs in turn produce small membrane-bound particles, our literature describes the ability of EVs to modulate the immune response in the inflammatory environment of damaged joint tissue. We then describe three sources of MSCs, each of which has unique characteristics and therapeutic potential. The advantages and disadvantages of each source are illustrated in terms of safety, efficacy, donor differences, tissue culture, and dosage. We then provide a further overview of techniques for engineering MSCs, from gene editing to the widespread use of targeted nanotechnology to address the homing effect of MSCs, followed by the emergence of 3D printing to further facilitate the regeneration and repair of cartilage tissue. The challenge of MSC heterogeneity requires even more research for clinical application, as MSCs from different sources, culture conditions, and functional subpopulations exhibit significant differences in therapy, leading to fluctuations in efficacy. Studies have shown that MSCs can exhibit different levels of efficacy depending on their source, and a reduction in efficacy can be observed after three months as they are metabolized in the body. The most important issue is the safety of MSCs. Although current clinical trials have not identified any adverse events, a few symptoms have been observed.

In conclusion, MSC therapies show great potential in the treatment of RA, but their clinical translation still faces many challenges. While existing studies have demonstrated the immunomodulatory and tissue repair capabilities of MSCs, the heterogeneity of efficacy and long-term safety need to be addressed through more rigorous clinical trials, as do standardized treatment regimens. Through the in-depth exploration of the mechanism of action of MSCs and the continuous optimization of therapeutic regimens, it is expected that, in the future, RA patients will be provided with more precise, safe, and efficient treatment options.

Acknowledgements

the authors declare that they have not used AI generated works in this article. This study is a retrospective review, which is not applicable to ethical review and does not need to be approved by clinical ethics.

Abbreviations

Atopic dermatitis

Adipose-derived mesenchymal stromal cells

Adverse Event

Serious Adverse Event

B lymphocyte Cells

Bone marrow

Bone marrow-derived mesenchymal stromal cells

Bone Marrow Stromal Cells-derived Exosomes

Chimeric antigen receptor T-cell immunotherapy

Chronic cerebral ischemia

Crohn’s disease

Collagen-induced arthritis

Cerebral Ischemia-Reperfusion Injury

Clustered regularly interspaced short palindromic Repeats-associated protein 9

Difficult-to-treat rheumatoid arthritis

Disease Activity Score 28

Dendritic cells

Disease-modifying anti-rheumatic drugs

Extracellular Matrix

Extracellular Vesicles

Fibroblast-like synoviocytes

Hepatocyte growth factor

Indoleamine2, 3-dioxygenase

Interleukin 10

Interleukin-1β

Janus Kinase

Pro-inflammatory macrophages

Anti-inflammatory macrophages

Mesenchymal stromal cells

Methotrexate

Nitric oxide

Nonsteroidal Anti-inflammatory Drugs

Osteoarthritis

Proprotein convertase subtilisin/kexin type 9

Prostaglandin E2

Placental-derived Mesenchymal stromal Cells

Rheumatoid arthritis

Spinal cord injury

Sensorineural hearing loss

T lymphocyte Cells

Traditional Chinese medicine

Transforming growth factor-β

T helper cell

Necrosis factor-α

Regulatory T cells

Umbilical cord blood-derived Mesenchymal stromal Cells

Author contributions

Shiyi Wu: writing–original draft, bibliographic review, writing tables; Shuaijie Ding: writing–original draft, writing–review and editing, conceptualization, data curation; YuWang: writing–original draft, bibliographic review, writing–review and editing; Shinan Li: writing–review and editing.

Funding

This study was supported by Scientific Research Special Fund Project of Zhejiang Association of Rehabilitation Medicine (ZKKY2024002), Zhejiang Foundation For Disabled Persons.

Data availability

Data permission for this study was obtained with the consent of the corresponding author.

Declarations

Ethics approval and consent to participate

This review is not applicable.

Consent for publication

Consent for publication was obtained from the participants.

Competing interests

The authors declare that they have no conflicts of interest.

Footnotes

Publisher’s note

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

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Associated Data

Data Availability Statement

Data permission for this study was obtained with the consent of the corresponding author.