A Review on Treatment of Premature Ovarian Insufficiency: Characteristics, Limitations, and Challenges of Stem Cell versus ExosomeTherapy

Table 1

Various types of MSCs application in POI treatment.

Type of MSCs	Route of administration	Amount of administration	Administered drug to induce POF	Effect	Limitation	Animal model	Ref
Human umbilical cord mesenchymal stem cell (HUC-MSCs)	Tail veins intravenously (IV), twice	1 × 10^6	120 mg/kg of CTX and 30 mg/kg busulfan	Antiapoptotic and anti-inflammatory, inhibition of GC apoptosis and inflammation	Unknown administration frequency, undetermined fate of UC-MSCs in vivo, and undetermined pharmacokinetics of UC-MSCs in vivo	Mice	[13]
HUC-MSCs	Tail veins (IV)	1 × 10^6	Cisplatin for 7 days, 2 mg/kg of cisplatin (intraperitoneally)	Enhance follicular development and restore the ovarian function, inhibit theca interstitial cells apoptosis by regulating NR4A1-mediated mitochondrial mechanisms		Rat	[17]
HUCMSCs	Tail veins (IV)	2 × 10^6	30 mg/kg busulfan and 120 mg/kg CTX	Recovered disturbed hormone secretion, FSH, and AMH	Need further investigations to confirm the mechanism involved in the ovarian function recovery	Mice	[18]
HUCMSCs	IV and in situ	25 μL, at a concentration of 2 × 10^6/mL UC-MSCs in situ 1 × 10^6/mL intravenously with a microinjector	200 mg/kg of CTX on the first day and then 8 mg/kg/day for the 15 consecutive days	Recovered disturbed hormone secretion and folliculogenesis	Restoration of the ovarian function takes place to some degree, tumorigenic potential of stem cells therapy, follow the ultimate fate of these cells, investigate the fertility of the rat model following our current CTX administration protocol and UC-MSCs therapy and require better understanding of the exact mechanism	Rat	[14]
HUCMSCs	Tail vein (IV)	5 × 10^6	50 mg/kg CTX on the first experiment day, followed by 8 mg/kg/day for 14 days	Partially recovered disturbed hormone secretion and folliculogenesis via the NGF/TrkA signaling pathway	Tumorigenicity of these cells, requires deeper investigations to better understand the exact underlying mechanism and the safety of the therapeutic effects of UC-MSCs on POF	Rat	[15]
Ovarian stromal stem cells (OSSCs)	Intraperitoneally the second and ninth days of the study	4 × 10^6	A dose of 200 mg/kg of CTX	Follicle maturation	The source of OSSCs, no standardization different for chemical agents and their concentrations, investigate the cytotoxicity of applied agents, generate the effective and standardized method	Rat	[19]
Bone marrow derived mesenchymal (BMMSCs)	Intraperitoneally the second and ninth days of the study	4 × 10^6	A dose of 200 mg/kg of CTX	Follicle maturation	The source of OSSCs, no standardization different for chemical agents and their concentrations, investigate the cytotoxicity of applied agents, generate the effective and standardized method	Rat	[19]
BMMSCs	On day 4 after CTX injection through the tail vein	0.5 × 10^6	A dose of 80 mg/kg of CTX	A drop in estradiol and rise in follicle-stimulating hormone and E2 levels	Should be repeated in a more tightly controlled way	Mice	[20]
BMMSCs	The day after CTX injection (days 9 and 16) intraperitoneally	4 × 10^6/kg	CTX 200 mg/kg intraperitoneally on the eighth and fifteenth days of the study	Be protective from germ cell apoptosis and DNA damage	The transplanted rats observed for only two weeks. Need to follow for long-term effects of the treatment	Rat	[21]
BMMSCs	Directly injected into the bilateral ovaries	2 × 10^6	50 mg/kg of CTX on the first day, then 8 mg/kg/day for 13 consecutive days (a total of 14 doses)	Be protective from germ cell apoptosis and DNA damage, a drop in estradiol and rise in follicle-stimulating hormone and E2 levels	BMSCs-secretome is likely responsible for the therapeutic paracrine effect of BMSCs. Stem cell secretome is expected to overcome the limitations of stem cell transplantation and become the basis of a novel therapy for ovarian damage	Rat	[22]
Human endometrial mesenchymal stem cells (EnSCs)	Tail vein	2 × 10^6	Intraperitoneal injection of busulfan (30 mg/kg; and CTX 120 mg/kg)	Reducing the depletion of the germline stem cell (GSCs) pool induced by chemotherapy		Mice	[23]
Human menstrual blood-derived stromal cells (MenSCs)	Through tail vein injection in seven days after CTX treatment	1 × 10^6	Intraperitoneal injection of 70 mg/kg CTX at the age of seven weeks	Regulating normal follicle development and estrous cycle, reducing apoptosis in ovaries to maintain homeostasis of microenvironment and modulating serum sex hormones to a relatively normal status. Participated in the activation of ovarian transcriptional expression in the ECM-dependent FAK/AKT signaling pathway and thus restoring the ovarian function to a certain extent		Mice	[24]
Human embryonic stem cell-derived mesenchymal stem cells (hES-MSCs)	Tail vein	5 × 10^6	2 mg/kg cisplatin daily for 10 days	Folliculogenesis be protective from germ cell apoptosis		Mice	[25]
HES-MSCs	IV	1 × 10^6	100 mg/kg CTX for 10 consecutive days	Restored the injured ovary by cytokine suppression of granulosa cell apoptosis and increased the follicular growth		Mice	[26]
HAMSCS	Intraperitoneally	1 × 10^6	The bilateral ovaries were burned for 30 s∼1 min with 10% hydrogen peroxide	Recovery of the estrus cycle, estrogen levels increased, while follicle-stimulating hormone levels decreased. Increasing of the ovarian index, fertility rate, and population of follicles at different stages. No obvious deformity in newborn mice and showing normal growth and development		Mice	[27]
Fetal liver mesenchymal stem cells	IV	1 × 10^6 FMSCs 2 weeks after CTX injection	A single intraperitoneal injection of CTX, 120 mg/kg injected everyday continued for 2 weeks	Preventing CTX-induced follicle loss and recovering sex hormone levels. Decreasing oxidative damage, increasing oxidative protection, improving antiapoptotic effects, and inhibiting apoptotic genes. Stimulating the activity of POI hGCs by targeting MT1		Mice	[28]
Adipose-derived stem cells	IV and in situ	1 × 10^6 (IV), 1 × 10^5 (injected directly into the bilateral ovaries)	50 mg/kg CTX for 15 consecutive days of injection	Increasing the population of follicles at different stages and ovulation		Mice	[29]
Adipose-derived mesenchymal stem	Injected locally into the ovary	5 × 10^4	50 mg/kg CTX on the first day and at 8 mg/kg during the following 13 day	Inhibiting the loss of mTOR and p-mTOR signaling, which is key to meiosis in oocytes		Rat	[30]
Human chorionic plate-derived mesenchymal stem cells	Intravenously transplanted into the mice once a week for 4 weeks	2 × 10^6 cells/kg	50 mg/kg CTX for 15 consecutive days	A drop in estradiol and rise in follicle-stimulating hormone and E2 levels and folliculogenesis		Mice	[31]
Clonal mesenchymal stromal cells	Intravenously transplanted into the mice	100 μl of PBS containing 1 × 10^6 cells	50 mg/kg CTX for 15 consecutive days	Protection of granulosa cells from CTX-induced damage, improvement in the angiogenesis via upregulation expression of VEGF and IGF1 at the mRNA level and VEGF and αSMA at the protein level, inhibition of apoptosis through the PI3K/AKT signaling pathway	The effective dose requires further study for clinical trials	Mice	[32]
Human ESC-MPCs with PLGA/hyaluronic acid (HA) sponge	Intravenous injection or local administration	5 × 10^6 cells/50 μL PBS and 50 μL HA gel	Cisplatin (2.0 mg/kg) for 10 days	Prolonging the cell survival rate in vivo. Recovered ovarian functions, including a significantly increased number of ovarian reserves, estrogen levels, and AMH levels and decreasing apoptotic levels. Improving the quality of oocytes and embryos and estrous cycle regularity		Mice	[33]
Human umbilical cord mesenchymal stem cell	Patients	0.5 × 10^7/100 μL, at three points, with 35 μL of UC-MSCs per point		Increased follicular development and improved egg collection	More investigation to confirm the duration of stem cells efficacy, distinguishing more appropriated clinical cases fit for this therapy, validating the dose of UC-MSCs	Human	[34]
Umbilical cord–derived mesenchymal stem cells on a collagen scaffold	Suspensions (10 μl) were injected into the core of the ovaries	2 × 105 UC-MSC in 10 μl degradable collagen	CTX (40 mg/kg/day) for 15 consecutive days	Promoting ovarian angiogenesis with the increased expression of CD31	Unknown mechanism of interaction between collagen scaffolds and stem cells remains. Choose a proper density of stem cells on a collagen scaffold to allow cell to distribute evenly. Requires further investigation of the potential underlying mechanism of collagen scaffolds in UC-MSCs growth after transplantation	Mice	[35]
Umbilical cord mesenchymal stem cells on a collagen scaffold (collagen/UC-MSCs)	Patients	5 × 10^6/400 μL for unilateral ovarian injection, collagen concentration, 5 mg·mL^−1		Rescuing overall ovarian function, elevating estradiol concentrations, improving follicular development, and increasing number of antral follicles. Successful clinical pregnancy in women with POF after transplantation of collagen/UC-MSCs or UC-MSCs		Human	[36]