Table 1 Preclinical study of stem cell therapy on POF

UCMSC

■ UCMSCs restore the ovarian function after paclitaxel injection through a direct triggering effect on the ovarian epithelium and/or indirect enrichment of ovarian niche through regulating tissue expression of CK 8/18, TGF-ß and PCNA (epithelial tissue, growth factor etc)

injection of HCB-MSCs

[31]

■ UCMSCs restore disturbed hormone secretion and folliculogenesis by reducing GC apoptosis. UCMSCs could reside in ovarian tissues and could survive for a comparatiely long time without obvious proliferation.

1 × 10⁶ UCMSCs intravenous injection

[32]

■ UCMSC treatment restores ovarian function by increasing follicular number, decreasing FSH serum and increasing AMH serum

5 × 10⁵ UCMSCs injected via intraovarian route

[33]

■ UCMSCs could reduce ovarian failure due to premature senescence caused by chemotherapy, and the NGF/TrkA signaling pathway was involved in the amelioration of POF.

5 × 10⁶ UCMSCs injected intravenously

[34]

■ Serum levels of E2, LH, VEGF in hAMSC and UCMSC transplanted groups were greater and FSH level was lower. Transplantation restored damaged ovarian function.

1 × 10⁶ UCMSCs and h-AMSCs intraovarian injection

[24]

BMMSC

■ Estradiol level dropped and FSH level rised 21 days after MSC therapy Damaged ovaries after chemotherapy regain functions after transplantation.

0.5 × 10⁶ BMMSCs injected through the tail vein

[23]

■ BM-MSC transplantation produces healthier ovarian follicles and less apoptosis of ovarian cells

1 × 10⁶ BM-MSCs injected via tail IP

[35]

■ The significant reduction of atretic follicle and significant increase of antral follicle and secondary follicle were observed in ovaries of BMSCs-treated mouse. mRNA expression levels of Nano3, Nobox, Lhx8 increased.

2 × 10⁶ BMMSCs injected via tail vein

[36]

■ Restore ovarian hormone production (FSH, AMH), reactivate folliculogenesis

5 × 10⁵ BMSCs injected via intraovarian route

[13]

■ BMMSC treatment resulted in higher numbers of preovutory follicles, metaphase II oocytes, 2-cell embryos, promoted ovarian vascularization, reduced apoptosis

1 × 10⁶ BMMSCs IP injection

[37]

FGSCs

■ Transplanted FGSCs restored function of premature ovarian failure and generated offspring in mice model.

1 × 10⁴ FGSCs injected

[30]

MenSCs

■ MenSC reduce apoptosis in granulosa cells, reduce fibrosis of ovarian interstitium, increase follicular numbers, reparative effects on damaged ovaries by secreting FGF2

2x10⁶MenSCs

[26]

■ MenSCs regulate normal follicle development, estrous cycle, reduce apoptosis in ovaries and activate ovarian transcriptional expression in ECM-dependent FAK/AKT signaling pathway

1x10⁶MenSCs IP injection

[6]

CP-MSCs

■ Restored serum hormone level and ovarian function

2 × 10⁶ chorionic plate-derived MSCs injected via tail vein

[38]

hPMSC

■ Inhibits granulosa cell apoptosis and follicular atresia by upregulating expression of AMH and FSHR in granulosa cells

1x10⁶hPMSCs injected via tail vein

[25]

■ hPMSC transplantation induces ZP3 immunization and restores ovarian function associated with PI3k/Akt signal pathway

1 × 10⁶hPMSCs IP injection

[39]

■ hPMSC transplantation reduces apoptosis of GC by regulating the expression of IRE1-alpha pathway of ER stress in ovaries

1 × 10⁶ hPMSCs injected via tail vein

[40]

■ PBMCs combined with PRP restore ovarian function by increasing ovarian neovascularization, folliculogenesis and reducing GC apoptosis

4 × 10⁶ PBMCs IP injection

[41]

ADSCs

■ Exosomes derived from hADSCs improve ovarian function by improving follicle numbers and inhibiting apoptosis rate

1x10⁶hADSCs injected via intraovarian route

[27]

■ Adipose tissue-derived MSCs improve follicular count, AMH and E2 levels, and related gene expressions (CXCL12, BMP-4, TGF-β, IGF-1)

1 × 10⁶AT-MSCs IP injection

[42]

■ ADSCs transplantation on collagen scaffolds improved fertility of rats with ovarian damage.

2 × 10⁶ ADSCs injected via intraovarian route

[43]

hAD-MSCs

■ hAD-MSCs inhibit chemotherapy-induced GC apoptosis, promote angiogenesis, regulate follicular development by upregulating Bcl-2 expression.

4x10⁶hADMSCs IP injection

[28]

BMMSC, OSC

■ The in-vivo transplantation of OSCs can be more effective protectors than BMMSCs for follicle maturation after chemotherapy. Unfortunately, the source of OSSCs is still a limitation for clinical applications.

2 × 10⁶ BMMSCs and OSSCs injected intraperitoneally

[44]

hUCMSC

■ hUCMSC increase E2 and AMH, decrease FSH. Improves follicle number and expression of HGF, VEGF, IGF-1

1x10⁶hUCMSCs injected via tail vein

[14]

hAMSC, hAEC

■ hAMSCs are more effective in improving ovarian function than hAECs based on its telomerase activity, pluripotent marker expression levels, cytokine secretion.

Intraovarian injection

[45]

hADSC

■ HGF and bFGF derived from hADSCs improved ovarian function during natural aging via reduction of oxidative stress by activating the SIRT1/FOXO1 signaling pathway.

Intraovarian injection

[15]

BMSC

■ intra-ovarian injection of BMSCs changed the gene expression but did not recover granulosa cells or ovarian tissue.

1 × 10⁷ BMSCs intraovarian injection

[22]

hEPC

■ hEPCs attenuates reproductive aging and dysfunction potentially via regulation of inflammation, apoptosis and ER stress.

5x10⁴hEPCs injected via tail vein

[46]

AFSC

■ AFSC-derived exosomes contain miR-146a and miR-10a which inhibit apoptosis in damaged GCs and prevent ovarian follicles from atresia

Direct injection

[47]

miR-21-MSCs

■ miR-21 overexpression in MSC decreases apoptosis, downregulate PTEN and PDCD4, icrease E2, decrease FSH.

1 × 106 MSCs injected into the bilateral ovaries

[48]

hAEC exosomes

■ hAEC exosomes increased number of follicles, inhibited GCs apoptosis by transferring miR-1246 which targets the apoptosis pathway.

1.6 × 10⁹ particles injected via tail vein

[49]

ADSCs

■ Adipose derived mesenchymal stem cells can prevent the destructive effects of ischemia reperfusion injury on grafted ovaries through reducing oxidative stress and inflammation leading to improvement in the follicular pool and the endocrine function of the autografted ovaries.

5 × 10⁴ ADSCs injected via intraovarian route

[55]

PD-MSC

■ Spheroid-cultured PD-MSC transplantation increases estrogen and folliculogenesis-related gene expressions in Ovx rats

1 × 10⁶ PD-MSC harvested, 100,000 cells directly injected into ovary

[50]