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] |