Mesenchymal stem cells for recurrent miscarriage.

BACKGROUND: Recurrent pregnancy loss (RPL), affecting 1–5% of couples, is frequently driven by immunological dysregulation, including excessive natural killer (NK) cell cytotoxicity, reduced regulatory T cell (Treg) function, Th1/Th17 dominance, and inflammatory cytokine imbalance at the maternal-fetal interface. These abnormalities disrupt immune tolerance to the semi-allogeneic fetus, leading to implantation failure or early miscarriage. Current interventions (e.g. low-dose aspirin/heparin for antiphospholipid syndrome, intravenous immunoglobulin, or corticosteroids) show variable efficacy and limitations, particularly in unexplained cases. Mesenchymal stem cells (MSCs), with proven immunomodulatory, anti-inflammatory, and tissue-repair properties, have gained regulatory approval for severe immune dysregulation conditions like steroid-refractory graft-versus-host disease (GVHD), which shares pathophysiological parallels with immune-mediated RPL, including NK hyperactivity and deficient Treg tolerance. MAIN BODY: MSCs from sources such as bone marrow, adipose tissue, or umbilical cord exert context-dependent effects, secreting anti-inflammatory factors (e.g. IL-10, TGF-β), suppressing pro-inflammatory cytokines, inhibiting cytotoxic NK activity, and promoting Treg expansion and function to restore immune homeostasis. Preclinical studies in abortion-prone mouse models (e.g. CBA/J × DBA/2) demonstrate that MSCs reduce fetal resorption by attenuating inflammation, enhancing placental angiogenesis, and balancing decidual immune responses. Emerging human data support MSCs for uterine repair in conditions like thin endometrium or Asherman syndrome, improving endometrial thickness and pregnancy outcomes. Unlike broad immunosuppressants, MSCs offer targeted, responsive modulation with low immunogenicity, minimal tumorigenicity, and potential for autologous or allogeneic use via simple infusion routes. CONCLUSION: MSCs represent a promising, novel therapeutic strategy for immunologically mediated RPL by addressing core immune imbalances and supporting placental/tissue health, potentially outperforming existing options in unexplained cases. Building on FDA-approved MSC therapies for analogous immune pathologies and encouraging preclinical results, clinical investigation of MSC-based interventions is warranted to establish safety, efficacy, and optimal protocols for this challenging condition. CLINICAL TRIAL NUMBER: Not applicable.