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

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.