Advances in human umbilical cord mesenchymal stem cells-derived extracellular vesicles and biomaterial assemblies for endometrial injury treatment

Table 1 Summary of different mesenchymal stem cell types in endometrial injury treatment

MSC type	Source	Mechanisms in endometrial repair	Key findings in endometrial injury studies	Ref.
Umbilical cord-derived MSCs	Endometrium	Proliferation, anti-fibrosis, angiogenesis	Support for endometrial regeneration by differentiating into functional endometrial cells	[85]
Bone marrow-derived MSCs	Bone marrow	Anti-inflammation, immunomodulation	Reduction of fibrosis and improvement in endometrial thickness and vascularization in preclinical models	[86]
Adipose tissue-derived MSCs	Adipose tissues	Paracrine signaling, anti-apoptosis	Significant potential in mitigating fibrosis and enhancing cellular regeneration	[87]
Amniotic MSCs	Amniotic membranes	Immunomodulation, anti-fibrosis	Success in reducing inflammation and supporting tissue repair of the endometrium in experimental settings	[88]
Menstrual blood-derived MSCs	Menstrual blood	Angiogenesis, epithelial-mesenchymal transition	Known for high proliferative potential and efficacy in improving endometrial receptivity and vascular repair	[89]

MSC: Mesenchymal stem cell.

Table 2 A summary of the literature on human umbilical cord mesenchymal stem cells and their exosomes in endometrial injury repair

No.	MSC origin	Vehicle type	Carrier	Stem cell transplant method	Model	Target (gene/pathway)	Biological functions	Reproductive outcome	Ref.
1	HucMSC	NA	HA/Gel hydrogel	Intrauterine injection	Endometrial mechanical injury rat	MEK/ERK1/2	Fibrosis; inflammation; migration; proliferation	Endometrial thickness; number of glands; endometrial vessels; embryo implantation rate; live birth rate	[30]
2	HucMSC	NA	NA	NA	HESC	CCL2, HGF	Migration; invasion	NA	[90]
3	HucMSC	Exosome	NA	Femoral vein injection	Endometrial 95% ethanol injury rat	MiR-202-3p/MMP11	ECM remodeling	NA	[65]
4	HucMSC	NA	GelMA/SerMA	Intrauterine injection	Endometrial 95% ethanol injury mouse	CD31, CK18, Ki67, vimentin, caspase 3	Angiogenesis; proliferation; apoptosis; fibrosis	Endometrial thickness; embryo implantation rate	[58]
5	T10-HucMSC	Exosome	NA	Intrauterine injection	HESC treated with TGF-β endometrial mechanical injury rat	MiR-543N-cadherin α-SMA FN1	Fibrosis; EMT; differentiation; apoptosis; migration	NA	[59]
6	HucMSC treated with TGF-β1	Exosome	Cross-linked sodium hyaluronate	Intrauterine injection	Endometrial 95% ethanol injury rat	TGF-β1/Smad2/3	Angiogenesis; fibrosis; proliferation; migration; collagen remodeling	Endometrial thickness; number of glands; embryo implantation rate	[60]
7	HucMSC	Exosome	NA	NA	EEC injury induced by hypoxia	MiR-663a/CDKN2A	Proliferation; apoptosis; migration; EMT	NA	[61]
8	T10-HucMSC	Exosome	NA	Intrauterine injection	Endometrial 95% ethanol injury mouse	HOXA10	Fibrosis; angiogenesis; apoptosis	Endometrial thickness; number of glands; embryo implantation rate; Endometrial receptivity	[62]
9	UC-MSCbFGF	NA	Collagen scaffolds	Intrauterine injection	Uterine full-thickness defect rat	NA	Inflammation; angiogenesis; proliferation; regeneration	Endometrial thickness; embryo implantation rate	[91]
10	HucMSC	NA	PF-127	Intrauterine injection	Endometrial 95% ethanol injury rat	IL-1β, bFGF, EGF, HGF	Angiogenesis; inflammation; fibrosis	Endometrial thickness; number of glands	[65]
11	HucMSC	NA	SF-SIS scaffolds	Transplanted in situ	Uterine full-thickness defect mouse	circPTP4A2/miR-330-5p/PDK2	Fibrosis; mitochondrial metabolism	Number of glands; endometrial fibrosis area	[66]
12	HucMSC	NA	NA	Tail vein injection versus intrauterine injection	Endometrial 95% ethanol injury rat	IL-1β, TNF-α, bFGF	Angiogenesis; inflammation	Number of glands; endometrial receptivity	[92]
13	HucMSC	Exosome	NA	Tail vein injection	Mifepristone-induced HESC injury endometrial 95% ethanol injury rat	Integrin alpha, thrombospondin, laminin, collagen, VWF	ECM remodeling; protein degradation and absorption; inflammation; proliferation; apoptosis; migration; adhesion	Endometrial morphology and thickness; number of glands; endometrial fibrosis area; embryo implantation rate	[68]
14	HucMSC	NA	NA	NA	Endometrial mechanical injury mouse	MiR-455-5p/SOCS3/JAK/STAT455	Fibrosis; proliferation; cell cycle progression	Number of glands; endometrial fibrosis area	[69]
15	HucMSC	NA	AAM	Transplanted in situ	Endometrial 95% ethanol injury rat	Keratin, vimentin, integrin β3, VEGF, MMP9	ECM remodeling; proliferation; migration; inflammation	Endometrial morphology and thickness; number of glands; endometrial receptivity; pregnancy rate; birth weight; number of neonatal rats	[70]
16	HucMSC	NA	Collagen scaffolds	Hysteroscopic transplantation	16 females experiencing infertility with thin endometrium (embryo transfers ≤ 5.5 mm)	ERα, PR	Angiogenesis; proliferation; hormone response; differentiation; angiogenesis	Endometrial thickness; uterine receptivity (endometrial volume and subendometrial blood flow); number of glands; miscarriage rate; pregnancy rate; live birth rate; birth defects	[55]
17	HucMSC	NA	NA	Intraperitoneal injection	Endometrial mechanical injury rat	TGF-β1/Smad3	Fibrosis; angiogenesis; differentiation; migration	Endometrial thickness; endometrial fibrosis area; number of glands; pregnancy rate; number of fetuses	[93]
18	HucMSC	Exosome	Collagen scaffolds	Transplanted in situ	Endometrial mechanical injury rat	MiR-223-3p	Immunomodulation (infiltration and polarization of macrophages); collagen remodeling; hormone response; inflammation; endometrial regeneration; fibrosis; angiogenesis	Pregnancy rate	[71]
19	HucMSC	NA	HA-GEL	Transplanted in situ	Endometrial mechanical injury rhesus monkey	IL-4, IGF-1, EGF, IFN, VEGF	Fibrosis; angiogenesis; inflammation	Endometrial morphology and thickness; number of glands; endometrial receptivity	[84]
20	HucMSC	NA	Collagen scaffolds	Intrauterine injection	Endometrial mechanical injury rat	ER, CTGF, TGFβ1, FGF2	Proliferation; hormone response; fibrosis	Number of glands; endometrial fibrosis area	[94]
21	HucMSC	Exosome	NA	NA	OGD/R-induced injured EEC	TLR4/RelA	Cell viability; cell death; inflammation	NA	[95]
22	HucMSC	NA	Collagen scaffolds	Transplanted in situ	HESC endometrial mechanical injury rat	TGF-b1, PDGF-BB, VEGF-A, Ki67	Proliferation; apoptosis; hormone response; regeneration; collagen remodeling; fibrosis; angiogenesis	Endometrial morphology and thickness; number of glands; pregnancy rate	[96]
23	HucMSC	NA	Collagen scaffolds	Transplanted in situ (spread onto an 18F Foley catheter and placed into the uterine cavity)	26 females experiencing infertility with recurrent IUA	ERα, vimentin, Ki67, VWF, ΔNP63	Proliferation; differentiation; angiogenesis	IUA score; endometrial thickness; ongoing pregnancy rate (> 12 weeks active fetus); live birth rate; menstrual volume; miscarriage rate; histological changes in endometrium	[97]
24	HucMSC	NA	NA	Tail vein injection	Endometrial 95% ethanol injury rat	VEGF-A, MMP9, IFN-γ, TNF-α, IL-2, α-SMA, TGF-β	Fibrosis; proliferation; angiogenesis; inflammation; differentiation; regeneration; fibrosis	Endometrial morphology and thickness; number of glands; endometrial fibrosis area; pregnancy rate	[98]
25	HucMSC	NA	Collagen scaffolds	Intrauterine injection	Uterine full-thickness defect rat	MMP-9, α-SMA, VWF	Adhesion; migration; differentiation; angiogenesis; differentiation	Endometrial morphology and thickness; number of glands; pregnancy rate; number, size, and weight of fetuses	[56]
26	HucMSC	Exosome	NA	NA	Mifepristone-induced HESC injury	PTEN/AKT	Proliferation; apoptosis	NA	[57]
27	HucMSC	Exosome	NA	NA	Mifepristone-induced HESC injury	MiR-7162-3p/APOL6	Apoptosis; regeneration	NA	[58]
28	HucMSC	Exosome	NA	NA	HESC treated with TGF-β1	MiR-145-5p/ZEB2	Fibrosis	NA	[54]
29	HucMSC	Exosome	NA	NA	HESC	NA	Proliferation	NA	[99]
30	WJMSC	NA	NA	Intrauterine injection	1 female experiencing infertility with IUA; 1 female experiencing infertility with endometrial atrophy	NA	NA	Endometrial thickness; pregnancy rate	[80]
31	WJMSC	NA	NA	NA	Mifepristone-induced HESC injury	Circ6401miR-29b-1-5p/RAP1B	Angiogenesis; apoptosis	NA	[100]
32	WJMSC	NA	NA	Intrauterine injection	Endometrial 95% ethanol injury rat	TGF-β1 Rho/ROCK	Angiogenesis; regeneration	Endometrial thickness; number of glands	[101]
33	hAMSC	NA	NA	NA	Mifepristone-induced HESC injury	VEGF, caspase 3, caspase 8	Proliferation; apoptosis	NA	[102]
34	hAMSC	NA	NA	Intrauterine injection	Endometrial 95% ethanol injury rat	Notch pathway	Differentiation; regeneration and repair	NA	[103]
35	hAMSC	NA	NA	Intrauterine injection	Endometrial mechanical injury rat	TNFα, IL-1β, bFGF, IL-6, VEGF	Angiogenesis; regeneration	Endometrial thickness; number of glands; endometrial fibrosis area	[52]

AKT: Protein kinase B; APOL6: Apolipoprotein L6; bFGF: Basic fibroblast growth factor; CCL2: C-C motif ligand 2; CTGF: Connective tissue growth factor; ECM: Extracellular matrix; EEC: Endometrial epithelial cell; EGF: Epidermal growth factor; EMT: Epithelial-mesenchymal transition; ER: Estrogen receptor; ERα: Estrogen receptor α; ERK1/2: Extracellular regulated protein kinases 1/2; FGF2: Fibroblast growth factor 2; hAMSC: Human amniotic mesenchymal stromal cell; HA: Hyaluronic acid; HESC: Human embryonic stem cell; HGF: Hepatocyte growth factor; HOXA10: Homeobox A10; HucMSC: Human umbilical cord mesenchymal stem cell; IFN: Interferon; IGF-1: Insulin-like growth factor-1; IL: Interleukin; IUA: Intrauterine adhesions; JAK: Janus kinase; MEK: Mitogen-activated and extracellular signal-regulated kinase; miR: MicroRNA; MMP: Matrix metalloproteinase; MSC: Mesenchymal stem cell; NA: Not available; PDGF-BB: Platelet-derived growth factor-BB; PR: Progesterone receptor; PTEN: Phosphatase and tensin homolog; SF-SIS: Silk fibroin small-intestinal submucosa; α-SMA: α-smooth muscle actin; Smad: Small mothers against decapentaplegic; STAT455: Signal transducer and activator of transcription 455; TGF-β: Transforming growth factor-β; TLR4: Toll-like receptor 4; TNF: Tumor necrosis factor; UC-MSC^bFGF: Umbilical cord-mesenchymal stem cells^{basic fibroblast growth factor}; VEGF: Vascular endothelial growth factor; VWF: Von Willebrand factor; WJMSC: Wharton jelly of umbilical cord; ZEB2: Zinc finger E-box binding homeobox 2 axis.