Innovations in the treatment of endometrial diseases: Role of human umbilical cord mesenchymal stem cells and their exosomes

Table 3 Comparative analysis and critical appraisal of therapeutic strategies for intrauterine adhesions

Strategy	Theoretical rationale/mechanism of action	Current best efficacy signal (source)	Key methodological limitations (source)	Unresolved translational challenges
hUC-MSCs alone (intrauterine perfusion)	Minimally invasive; direct delivery of viable cells and paracrine factors	Improved menstrual volume and endometrial morphology in a small, mixed cohort[64]	Very small, heterogeneous sample; no control group; IUA-specific pregnancy data not reported[64]	Low cell retention; optimal dose and timing undefined; durability of effect unproven
hUC-MSCs + collagen scaffold	Enhanced cell retention and survival; provides 3D structural support and a physical barrier against adhesion reformation	Live birth rate of 30.8% in patients with severe IUA[65]	Single-arm, open-label design; small sample size; follow-up ended at delivery (no long-term offspring data)[65]	Risk of fibrotic recurrence; necessity for long-term tumorigenicity monitoring; scaffold standardization (e.g., degradation kinetics, porosity)
hUC-MSCs + HA-GEL	Biocompatible anti-adhesion barrier; serves as a hydrogel carrier for sustained factor release; fosters an anti-inflammatory microenvironment	Significant endometrial regeneration and reduced fibrosis in a primate IUA model[79,80]	Efficacy in humans pending validation in large-scale trials with standardized reproductive endpoints	Defining the therapeutic window of gel residence and bioactivity; clinical cost-effectiveness analysis
hUC-MSC-exosomes + scaffold	Cell-free approach mitigates risks of live-cell transplantation; scaffold enables controlled release; potent immunomodulatory cargo	Restoration of fertility and induction of M2 macrophage polarization in a rat IUA model[81]	Awaiting clinical translation; challenges in exosome standardization and scalable GMP manufacturing	Potential immunogenicity of allogeneic exosomes; long-term biodistribution and safety profile; development of validated potency assays
hUC-MSC-exosomes + estrogen	Synergistic action: Estrogen priming optimizes endometrial receptivity, while exosomes deliver targeted regenerative signals	Superior anti-fibrotic and pro-angiogenic effects compared to monotherapy in a rat IUA model[82]	No clinical data available; long-term safety of combined therapy unknown	Mechanistic understanding of synergy; criteria for patient stratification; optimization of the combined dosing regimen

hUC-MSCs: Human umbilical cord-derived mesenchymal stem cells; IUA: Intrauterine adhesions; 3D: Three-dimensional; HA-GEL: Hyaluronic acid gel; GMP: Good manufacturing practice.