Mesenchymal Stem Cell Therapy for Thin Endometrium: Mechanisms, Delivery Strategies, and Clinical Outcomes: A Systematic Review

Thin endometrium constitutes a significant cause of infertility that demonstrates an inadequate response to conventional treatments, prompting the investigation of mesenchymal stem cell (MSC)-based regenerative therapies as alternative interventions. This systematic review, conducted in accordance with PRISMA guidelines, evaluated primary research from January 2020 to January 2026, analyzing fourteen studies that investigated MSC therapies across six cell sources and four delivery platforms for the treatment of thin endometrium. The findings demonstrate that umbilical cord-derived MSCs (UC-MSCs) exhibited superior therapeutic efficacy compared to other MSC sources, achieving restoration of endometrial thickness to 80–95% of control values with mean improvements of 2.4 mm, glandular regeneration yielding 20.9–24.8 glands per high-power field, pregnancy rates ranging from 60 to 80%, and substantial fibrosis reduction of 60–79%. Advanced delivery strategies significantly enhanced treatment outcomes; specifically, hydrogel encapsulation using Pluronic F-127 or hyaluronic acid extended MSC retention 4.7-fold—from 3 to 14 days—compared to direct injection, which correlated with a 23% greater improvement in endometrial thickness. Concurrently, scaffold-based delivery provided comparable efficacy while offering additional three-dimensional structural support. Mechanistic investigations revealed that MSC therapies activate five coordinated regenerative pathways: VEGF-mediated angiogenesis with 2.5–3.8 fold upregulation, TGF-β/Smad anti-fibrotic signaling that decreases TGF-β1 by 2.9–3.2 fold, the STAT3 proliferation pathway with a 3.8-fold increase, SDF-1/CXCR4 chemotactic signaling enhanced by 1.8-fold, and immunomodulation promoting M2 macrophage polarization with a 62% reduction in pro-inflammatory cytokines. Notably, MSC-derived exosomes demonstrated therapeutic potential equal to or exceeding that of cellular preparations; UC-MSC exosomes achieved a 23% greater increase in thickness and 80% pregnancy rates versus 60% for cellular formulations. A single clinical pilot study involving five patients with refractory Asherman syndrome utilizing collagen scaffold-delivered UC-MSCs reported encouraging outcomes, including an 81% improvement in endometrial thickness (from 4.2 ± 0.8 mm to 7.6 ± 1.2 mm), a 60% pregnancy rate, and a 40% live birth rate. Despite robust preclinical evidence supporting UC-MSC therapies delivered via biodegradable platforms for endometrial regeneration through multi-mechanistic pathways, clinical translation requires well-designed randomized controlled trials incorporating standardized manufacturing protocols, adequate statistical power, mechanistic biomarker validation, and comprehensive long-term safety monitoring before widespread implementation for treating thin endometrium-related infertility.