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

Table 1 Animal studies of human umbilical cord-derived mesenchymal stem cells and their derived exosomes in endometrial diseases

Species	Disease	Treatment	Administration	Key findings (↑ increase; ↓ decrease)	Ref.
Rabbit	IUA	hUC-MSCs	Uterine wall injection of 1 × 106 cells	↑ Gland number; ↑ ER & Ki-67 expression; ↓ fibrosis	[22]
Rat	IUA	hUC-MSCs	Intraperitoneal injection of 2 × 106 cells	↓ TGF-β1/Smad3 expression; ↑ CD31 (angiogenesis)	[24]
Mouse	IUA	Cytokine-preconditioned hUC-MSCs	Uterine wall injection of 2 × 104 cells	↓ TNF-α, IL-6, CD301+ macrophages, α-SMA, collagen I; ↑ IL-10; JAK-STAT pathway modulated	[25]
Mouse	IUA	hUC-MSCs	Tail vein injection of 1 × 106 cells	↓ Fibrosis; ↓ collagen deposition	[30]
Mouse	IUA	hUC-MSCs	Tail vein injection of 2 × 105 cells	Improved endometrial architecture; ↑ visible glands	[38]
Mouse	IUA	hUC-MSC-derived exosomes	Tail vein injection (equivalent to 2 × 106 cells)	↓ IL-1β & IL-6; ↑ M2 macrophage polarization; JAK-STAT pathway activated	[32]
Monkey	IUA	hUC-MSCs/HA-GEL	Intrauterine injection of 1-2 × 107 cells in 200 μL HA-GEL	↑ Endometrial thickness; ↑ gland number; ↓ fibrotic area	[80]
Rat	IUA	hUC-MSCs/HA-GEL	Intrauterine injection of 1 × 1010 cells with 300 μL HA-GEL	↑ Number of pregnancy sacs; ↓ inflammatory & fibrotic factors	[79]
Rat	IUA	hUC-MSCs/HA-GEL	Intrauterine injection of 3 × 105 cells in 1 mL HA-GEL	Uterine cavity expansion; ↑ endometrial thickness & glandular cavity; ↑ gland number	[92]
Mouse	IUA	hUC-MSCs/scaffold	Intrauterine injection of 1 × 106 cells with silk fibroin-submucosa scaffold	↑ Gland number; ↓ fibrotic area	[106]
Rat	IUA	hUC-MSC-exosomes/scaffold	Intrauterine injection of 3 × 1010 exosomes with collagen scaffold	Enhanced endometrial regeneration; ↑ fertility rate	[81]
Rat	IUA	hUC-MSC-exosomes + estrogen	Intraperitoneal injection of exosomes + oral estrogen	↓ Fibrosis; uterine cavity expansion; ↑ blood vessels & glands; ↓ TGF-β; ↑ VEGF	[82]
Rat	Thin endometrium	hUC-MSCs	Tail vein injection of 1 × 107 cells	Preserved endometrial structure; ↑ embryo implantation rate; ↓ fibrosis & inflammation; ↑ cell proliferation & vascularization	[26]
Rat	Thin endometrium	hUC-MSCs	Intrauterine injection of 1 × 107 cells	↑ Endometrial thickness, area & gland number; ↑ cell proliferation & angiogenesis	[29]
Rat	Thin endometrium	hUC-MSCs/hydrogel	Tail vein injection of 5 × 106 cells with pluronic F-127 hydrogel	↑ Endometrial thickness & gland number; ↑ neovascularization	[97]
Rat	Thin endometrium	hUC-MSCs/matrigel microspheres	Intrauterine injection of cell-laden microspheres	↑ Endometrial thickness; ↑ fertility rate (25% to 75%)	[98]
Rat	IUA	hUC-MSCs	Sublingual vein injection of 5 × 106 cells	↓ Endometrial fibrosis; ↑ gland quantity	[100]
Mouse	Thin endometrium	hUC-MSCs/hydrogel	Intrauterine injection of 1 × 106 cells in GelMA/SerMA hydrogel	↑ Endometrial thickness; ↓ fibrosis; improved endometrial repair	[101]
Mouse	Thin endometrium	hUC-MSCs/hydrogel	Intrauterine injection of 5 × 105 cells in alginate-rCo III hydrogel	Restored endometrial function; induced mesenchymal-epithelial transition; ↑ endometrial regeneration & fertility	[102]
Rat	Endometriosis	hUC-MSCs	Tail vein injection of 1 × 105 cells (3 doses)	↓ Nerve fiber density in lesions; ↓ pain symptoms	[43]

IUA: Intrauterine adhesion; hUC-MSCs: Human umbilical cord-derived mesenchymal stem cells; ER: Estrogen receptor; TGF-β: Transforming growth factor β; CD31: Cluster of differentiation 31; TNF-α: Tumor necrosis factor alpha; IL: Interleukin; α-SMA: Alpha-smooth muscle actin; JAK: Janus kinase; STAT: Signal transducer and activator of transcription; M2: Macrophage type 2; HA-GEL: Hyaluronic acid gel; VEGF: Vascular endothelial growth factor; GelMA: Gelatin methacryloyl; SerMA: Sericin methacryloyl; Alginate-rCo III: Alginate-recombinant collagen III.

Table 2 Human trials of human umbilical cord-derived mesenchymal stem cells in endometrial diseases

Patients (n)	Disease	Treatment & administration	Study design & follow-up	Primary outcomes	Limitations	Ref.
10	IUA (n = 6), cesarean scar diverticulum (n = 4)	hUC-MSCs, 2 × 107 cells, intrauterine infusion (× 2 cycles)	Phase I, open-label, 6 months	(1) Improved menstrual volume (4/10); (2) Increased endometrial thickness (6/10); and (3) Increased uterine cavity volume (6/10)	(1) Very small sample size (n = 10); (2) No control group; (3) Short follow-up (6 months); (4) Open-label, non-randomized; and (5) Heterogeneous patient population & endpoints	[64]
26	Recurrent, moderate-severe IUA	hUC-MSCs/collagen scaffold, 1 × 107 cells on scaffold, intrauterine	Phase I, open-label, 30 months	(1) Improved menstrual parameters; (2) Reduced IUA score; (3) Increased endometrial thickness & blood flow; (4) Pregnancy: 10/26 (38.5%); and (5) Live birth: 8/26 (30.8%)	(1) Small sample size; (2) Single-center, open-label; (3) No placebo control; and (4) Follow-up ended at delivery (no long-term offspring data)	[65]
18	Thin endometrium (Asherman’s)	hUC-MSCs/collagen scaffold, 1 × 107 cells on scaffold, intrauterine (× 2 cycles)	Pilot study, open-label. Until the pregnancy outcome	(1) Increased endometrial thickness, microvascular density, Ki67 index, estrogen receptor α, progesterone receptor; pregnancy (5/18); (2) Delivering healthy babies (3/18); (3) Pregnancy: 5/18 (27.8%); and (4) Live birth: 3/18 (16.7%)	(1) Small sample size; (2) Non-randomized, open-label; (3) Short follow-up (pregnancy-defined); and (4) Included only the scaffold-treated arm in this analysis	[66]
25	Refractory thin endometrium	hUC-MSCs/collagen scaffold (hUC-MSC/CS) vs saline/CS (control). Intrauterine implantation post-hysteroscopy	Single-center, randomized, double-blind, controlled trial. Follow-up for cLBR	(1) cLBR: 3/11 (27.3%) vs 1/13 (7.7%) (P = 0.30); (2) Clinical pregnancy: 5/11 (45.5%) vs 1/13 (7.7%) (P = 0.06); and (3) Trend toward improved outcomes; mechanism linked to cytokine pathways	(1) Small sample size per group (n = 11, 13); (2) Single-center design; (3) Primary outcome (cLBR) did not reach statistical significance; and (4) Follow-up focused on pregnancy (1-year safety reported)	[67]

IUA: Intrauterine adhesion; hUC-MSC: Human umbilical cord-derived mesenchymal stem cell; CS: Collagen scaffold; cLBR: Cumulative live-birth rate.

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.