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

Table 2

Various types of MSCs-derived exosomes application in POI treatment.

Type of MSCs	Route of administration	Amount of administration	Administered drug to induce POF	Effect	Limitation	Animal model	Ref
Embryonic stem cells-derived extracellular vesicles	The tail vein intravenously three times once every 2 days	1 × 10^8/mL	CTX 120 mg/kg and busulfan 30 mg/kg	Recovery of the levels of serum sex hormones to normal levels, increasement of follicles, reduction of the number of apoptotic cells, and improvement of ovarian function by regulating the PI3K/AKT signaling pathway		Mice	[49]
AFMSCs- exosomes carrying miRNA-21	Intraovarian injection	0.5 × 10^6	CTX (40 mg/kg)	Prevent the apoptosis phenomenon, induce the follicles regeneration and recover the ovary function in infertile rat through the phosphatase and tensin homolog (PTEN) and PI3K/PTEN pathway		Rat	[48]
AFMSCs- exosomes carrying miR10a	After CTX for 24 h, intra-ovarian injections	125 μg	Busulfan 20 mg/kg and CTX 200 mg/kg	Anti-apoptotic effect on CTX-damaged GCs		Mice	[50]
Amniotic fluid-derived exosomes	Intraovarian injection	10 μl	200 mg/kg CTX on the first day and then with 8 mg/kg/d consecutively for 14 days	Recover of the levels of serum sex hormones to normal levels; restoring the ovarian function through the TGF-β/Smads signaling pathway		Rat	[51]
CD44^+/CD105^+HAFSC-exosomes carrying miR-369-3p	Via the tail vein every 2 days for 4 weeks	1 × 10^6 exosomes	CTX 70 mg/kg for 1 week, and then, CTX injection intraperitoneally at a dose of 30 mg/kg for 2 weeks every 2 days	Downregulate the expression of YAF2, inhibit the stability of PDCD5/p53, and reduce the apoptosis of ovarian granulosa cells	Role of miR-369-3p in AFSCs is limited, exploration for multiplicity of mechanisms, low yield of exosome, production efficiency must be increased	Mice	[52]
HUCMSCs- exosomes carrying miRNA-17-5p	Intraovarian injections	10^11 particles/mL	A dose of 120 mg/kg CTX	Promoting proliferation of CTX-damaged GCs and ovarian cells, and alleviating ROS accumulation by delivering exosomal miR-17-5P and inhibiting SIRT7 expression		Mice	[53]
HUCMSCs- exosomes carrying MicroRNA-29a	Tail vein	Exosomes (125 μg dissolved in 100 μl PBS)	5 mg/kg cisplatin	Maturation of follicles, inhibition in GC apoptosis and activating the Wnt/β-catenin pathway	Limitation in number of animals	Mice	[54]
HUCMSCs- exosomes carrying miR-126-3p	A single dose via caudal vein after 14 days of injection of cisplatin	Of 400 μg exosomal proteins/200 μl PBS	Cisplatin (1 mg/kg) for 14 days	Promoting proliferation and inhibiting the apoptosis of OGCs PIK3R2/PI3K/AKT/mTOR axis in vitro, increasing E2 and AMH levels, increasing body and reproductive organ weights and follicle counts, and reduced FSH levels	Develop the exosome extraction strategies order to produce purer and higher volumes of membrane vesicles, use further test besides the morphologic and functional tests to evaluate ovary damage, evaluate the reproductive function in chemotherapy-induced POF models, need more experiments for any possible downstream molecules associated with miR-126-3p, follow the long-term effects of miR-126-3p-hucMSCs-exosomes and further evaluation of its efficacy and safety	Rat	[55]
HUCMSCs- -derived microvesicles	Injected into the vena caudalis	150 μg	Busulfan (20 mg/kg) and CTX (200 mg/kg)	Promoting the ovarian angiogenesis, and recovering the disturbed estrous cycle, improving the numbers of primordial, developing, and preovulatory follicles	Requiring the natural mating trial would provide supplementary evidence to prove the effect of MVs in restoring damaged ovarian, exploring the molecular mechanisms involved in the angiogenesis promoting effects	Mice	[56]
HUCMSC-exosomes	Tail intravenous injection	1 ml PBS containing 1 × 10^10 particles	CTX combined with busulfan	Alleviating ovarian injury, facilitating ovarian function restoration, and protecting fertility; improving the local microenvironment of ovarian tissue in POI rats through immune regulation, cellular viability, inflammation regulation, fibrosis, and metabolism			[57]
HADSC-exosomes		1 × 10^6	CTX, 120 mg/kg, for 2 weeks	Proliferation of oocytes and GCs, promoting the hormonal secretion and follicles differentiation by SMAD/TGFβ signaling		Mice	[58]
BMSC-derived exosome	Injected intraperitoneally every other day for 2 weeks	150 μg	50 mg/kg CTX on the first day and then with 8 mg/kg/d consecutively for 14 days	Recovering the estrus cycle, increasing the number of basal and sinus follicles in POF rats, increasing estradiol (E2) and anti-Mullerian hormone (AMH) levels, and reducing follicle stimulating hormone (FSH) and luteinizing hormone (LH) levels in the serum, preventing the ovarian follicular atresia via the delivery of miR-144-5p, by targeting PTEN		Rat	[59]
BMSC-derived exosome	Injected into the tail vein on the 1st, 5th, and 10th day after modeling	125 μg/100 μL PBS	5 mg/kg cisplatin	Target regulation of p53 to inhibit ovarian granulosa cell apoptosis		Mice	[60]
MenSCs-exosomes	Intraovary injection	25 μg	VCD (4-vinylcyclohexene diepoxide) for 15 consecutive days (80 mg/kg per day)	Promoting the ovarian reserve, serum hormones, and fertility	Further explorations require for the MenSCs-exosomes effects on oocyte-granulosa cross-talking or gap-junction, investigate the molecular mechanism, identify the active components of MenSCs-exosomes for improving ovarian function (such as protein or micro-RNA)	Rat	[61]
Clonal MSCs-derived extracellular vesicles	Intravenously transplanted into the mice	100 μl of PBS containing 400 μg EV	50 mg/kg CTX for 15 consecutive days	Protection of granulosa cells from CTX-induced damage, improvement of 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. EV20K is more cost-effective and feasible than EV110K	The full cargo and function of the isolated EVs are not yet well known. The effective dose requires further study for clinical trials	Mice	[32]
MenSCs-exosomes	Intraovary injection	50 μl conditional exosomes suspended in PBS with about 4.5 × 10^8 particles/ml	IP injection of 4-vinylcyclohexene diepoxide for 15 continuous days	Ameliorating granulosa cell apoptosis by regulating the SMAD3/AKT/MDM2/P53 pathway via delivery of thrombospondin-1		Rat	[62]