Table 1.

Preclinical animal trials using MSCs to treat POI

Animal model	Stem cell type (or derivatives)	Dosage	Delivery route	Results	References
CTX-induced Wistar–Imamichi rats	Adipose-derived MSCs (ADSCs)	2 × 106 cells	Intraovarian injection	ADSCs transplantation could induce angiogenesis and restore the number of ovarian follicles and corpus lutea in ovaries	[21]
CTX-induced C57/BL6 mice	ADSCs	1 × 106 cells, (Intravenous); 1 × 105 cells, (Intraovarian)	Intravenous and intraovarian injection	ADSCs transplantation could significantly upregulate the population of follicles at different stages and ovulation	[22]
CTX-induced white albino rats	Amniotic membrane-derived MSCs (AMMSCs) and ADSCs	5 × 106 cells	Intravenous injection	Both AMMSCs and ADSCs transplantation exert a significant therapeutic efficacy in chemotherapy-induced ovarian insult in rats; and AMMSCs transplantation exert higher therapeutic efficacy when compared to ADSCs	[23]
CTX-induced Wistar rats	Rat bone marrow-derived mesenchymal stem cells (BMSCs) overexpressing miR-21	1 × 106 cells	Intraovarian injection	After BMSCs transplantation, the ovarian weight and follicle counts increased; estradiol levels increased while FSH levels decreased, with less severe apoptosis of GCs	[24]
CTX-induced Sprague–Dawley (SD) rats	LIPUS-pretreated human AMMSCs	4 × 106 cells	Intravenous injection	LIPUS-pretreated AMMSCs transplantation is more advantageous for reducing inflammation, improving the local microenvironment, and inhibiting GC apoptosis induced by chemotherapy	[25]
Cisplatin-induced C57BL/6 mice	MenSCs	2 × 106 MenSCs on days 1 and 3 of the experiment	Intravenous injection	MenSCs transplantation could improve the ovarian microenvironment by reducing apoptosis in GCs and the fibrosis of ovarian interstitium, which contributes to increase the follicular numbers and return sex hormone levels to normal values	[26]
CTX-induced Wistar rats	Rat BMSCs	1 × l06 cells	Intraovarian injection	heat shock-pretreated BMSCs transplantation could cause an increase in ovary weight and the number of follicles at different stages of estradiol levels; and a decrease in FSH levels and apoptosis of GCs	[27]
CTX-induced C57/BL6 mice	Human chorionic plate-derived mesenchymal stem cells (hCPMSCs)	2 × l06 cells/kg	Intravenous injection	hCPMSCs transplantation restored the serum hormone level and ovarian function of CTX-induced POF mice	[28]
CTX-induced C57BL/6 mice	Menstrual Blood-Derived Stromal Cells	1 × 106 cells	Intravenous injection	Menstrual Blood-Derived Stromal Cells restore ovarian function by regulating normal follicle development and estrous cycle via regulating the ECM-Dependent FAK/AKT Signaling	[29]
Cisplatin-induced C57BL/6 mice	BMSC-derived exosomes	125 μg of exosomal proteins on the 1st, 5th, and 10th day after modeling	Intravenous injection	BMSC-derived exosomes improved the follicular morphology of POF mice and inhibited the expression of apoptosis-related protein in vivo; furthermore, BMSC-derived exosomes repressed cisplatin-induced GCs apoptosis and increased cells viability in vitro	[30]
Busulfan and CTX-induced ICR mice	UCMSC-derived microvesicles (UCMSC-MVs)	150 μg	Intravenous injection	UCMSC-MVs treatment could increase the body weight and number of ovarian follicles (primordial, developing, and preovulatory follicles), induce ovarian angiogenesis and recover the disturbed estrous cycle of POI mice	[31]
10% hydrogen peroxide induced BALB/c mice	Human AMMSCs	1 × 106 cells	Intraperitoneal injection	The estrus cycle was recovered after hAMSCs transplantation at 7 and 14 days. Estrogen levels increased, while FSH levels decreased. The ovarian index, fertility rate, and population of follicles at different stages were significantly increased. The newborn mice had no obvious deformity and showed normal growth and development. The normal offspring mice were also fertile	[32]
CTX-induced ICR mice	Fetal liver-derived MSCs (fMSCs)	1 × 106 cells	Intravenous injection	fMSCs transplantation could prevent CTX-induced follicle loss and recover sex hormone levels; significantly decrease oxidative damage, increase oxidative protection; enhance anti-apoptotic effects and inhibit apoptotic genes in vivo and in vitro	[33]
CTX-induced SD rats	BMSCs and BMSC-derived exosomes	1 × 106 cells every other day for 2 weeks; 150 μg of exosomal proteins	Intraperitoneal injection	Both BMSCs and BMSC-derived exosomes transplantation could significantly recover the estrus cycle, increase the number of basal and sinus follicles; and increase estradiol and anti-Mullerian hormone (AMH) levels, but reduce FSH and luteinizing hormone levels in serum	[34]
CTX-induced SD rats	Amniotic fluid mesenchymal stem cells (AFSCs); AFMSCs-derived extracellular vesicles (AFMSCs-EVs)	5 × 105 cells, 100 μg	Intraovarian injection	AFMSCs and AFMSC-EVs treatment equally restored total follicular counts, AMH levels, regular estrous cycles and fruitful conception, while it both diminished caspase 3 and PTEN levels	[35]
Surgically removing one of the ovaries in SD rats	Placenta-derived mesenchymal stem cells (PDMSCs)	5 × 105 cells	Intravenous injection	PDMSCs transplantation could significantly increase the levels of AMH, FSH, and estradiol; and more mature follicles, less atresia and restoration of expanded blood vessels in the ovaries of PDMSCs treated rat	[36]
Surgically removing one of the ovaries in SD rats	PDMSCs	5 × 105 cells	Intravenous injection	The levels of apoptotic factors were decreased and ovary function was improved following PDMSCs transplantation	[37]
Busulfan and CTX-induced C57BL/6 mice	UCMSCs with overexpressing HO-1	1 × 106 cells	Intraperitoneal injection	HO-1 overexpressed UCMSCs transplantation could recover the ovarian function, increase GCs’ viability and decrease their apoptosis	[38]
Cisplatin-induced ICR mice	Human embryonic stem cell-derived MSCs (hESC-MSCs)	5 × 106 cells	Intravenous injection	The primary and primordial follicle counts in the ovaries of hESC-MSC treated group were significantly improved, and the count of zona pellucida remnants was significantly reduced	[39]
CTX-induced C57BL/6 mice	UCMSC-derived exosomes (UCMSC-Exos)	1012 particles/ml	Intraovarian injection	UCMSC-Exos inhibited apoptosis of CTX-injured human GCs, alleviated oxidative stress and rescued ovarian phenotype and function	[40]
Busulfan and CTX-induced C57BL/6 mice	hESC-MSCs and BMSCs	1 × 106 cells respectively	Intravenous injection	hESC-MSCs were similar to BMSCs in that they could restore the structure of the injured ovarian tissue. Meanwhile, hESC-MSCs promoted of follicular development, fertility via a paracrine effect	[41]
CTX-induced Wistar rats	MenSCs	2 × 105 cells/10 μl	Intraovarian injection	CD 146 + MenSCs transplantation increased the number of developing follicles, decreased the number of atresia follicles, and improved ovarian fibrosis	[42]
4-vinylcyclohexene diepoxide- induced SD rats	MenSCs and MenSC- derived exosomes	5 × 105 MenSCs; 25 μg MenSCs- exosomes	Intraovarian injection	MenSCs- derived exosomes promotes follicular development, activates dormant follicles, and improves POI rats’ fertility	[43]
CTX-induced C57BL/6 mice	UCMSCs	5 × 105 cells	Intraovarian injection	UCMSCs promoted granulosa cell proliferation and ovarian vascularization	[44]
Busulfan and CTX-induced C57BL/6 mice	UCMSCs	2 × 106 cells	Intravenous injection	Multiple UCMSCs transplantations have a better effect on the recovery of ovarian function than single hUC-MSC transplantation in POF	[45]
Busulfan and CTX-induced C57BL/6 mice	UCMSCs	1 × 106 cells	Intravenous injection	UCMSCs transplantation improve ovarian function through anti-apoptotic and anti-inflammatory effects via a paracrine mechanism	[46]
CTX-induced SD rats	human umbilical cord blood platelet-rich plasma (ucPRP) and UCMSCs	35 μL ucPRP with 2 × 106 cells	Intraovarian injection	The combined application of HucMSCs and ucPRP increased the levels of serum E2, AMH, and FSH via promoted ovarian angiogenesis and proliferation and reduce the apoptosis of ovarian granulosa cells	[47]
CTX-induced C57BL/6 mice	hESC-MSCs	1 × 106 cells	Intravenous injection	hESC-MSCs reduced apoptosis in the follicles and increased the expression of AMH protein	[48]