Table 5 The transplantation of stem cells from neonatal tissues in the POF animal model

hUCMSCs

Rats

(8 weeks)

CTX

(1st, 200 mg/kg, 8 mg/kg for 14 days)

hUCMSCs (1 × 10⁶/mL) in 100 μL PBS

iv

Improve follicle development and hormone secretion;

Reduce ovarian cells’ apoptosis

NO Report

[75]

Mice

(6–7 weeks)

CTX

(120 mg/kg) + BF (30 mg/kg)

hUCMSCs (1 × 10⁶/mL) in 200 μL PBS

iv

Increase ovarian size and the number of primary and secondary follicles, decrease the number of atretic follicles;

Increase E2 secretion and decrease FSH levels;

Exert anti-apoptotic and anti-inflammatory effects

Activate AKT and P38 pathways;

Exert anti-apoptotic and anti-inflammatory effects

[76]

C57BL/6 (8 weeks)

ZP3

hUCMSCs (1 × 10⁶/mL)

iv

Increase serum E2, P, IL-4 levels, and decrease the levels of FSH, IFN-γ, IL-2;

Increase the total number of follicles and decrease atretic follicles

Restored impaired ovarian and endothelial function mediated by changes in the Th1/Th2 cytokine ratio

[77]

SD Rats (12 weeks)

CTX

(1st , 200 mg/kg, 8 mg/kg for 14 days)

hUCMSCs (5 × 10⁶/mL) in 500 μL PBS

iv

Restore the disorder of hormone secretion (increase E2 and AMH);

Restores follicle production and prevents the loss of secondary follicles);

Prolong estrous;

Improve pregnant rate and embryos numbers of POF rats

Improve ovarian failure via NGF/TrkA signaling pathway

[78]

Wistar rats

(180–220 g)

Paclitaxel (7.5 mg/kg for 1 weeks)

hUCMSCs (2 × 10⁶/mL) in 20 μL PBS

Orthotopically inject

Increase E2 and AMH, decrease FSH level;

Increase antral follicle count

Regulate the tissue expression of CK 8/18, TGF-ß and PCNA;

By directly triggering the ovarian epithelium and/or indirectly enriching the ovarian niche

[79]

SD Rats (8 weeks)

Freund’s complete adjuvant

1 mL hUCMSCs with low (0.25 × 10⁶), medium (1 × 10⁶) and high (4 × 10⁶) doses

iv

Restore estrous cycle;

Improve follicle development in rats;

Increased serum E2, P4 and AMH;

Reduce apoptotic granulomas and promote the proliferation of granuloma cells

Show dose-dependent effects on improving ovarian follicular development in POF rats

[13]

C57BL/6 (6–8 weeks)

CTX (120 mg/kg) + BF (30 mg/kg)

hUCMSCs (1 × 10⁶/mL) in 100 μL PBS

iv

Increase levels of FSH and E2 secretion,

Decrease follicular atresia, and increased the number of sinus follicles;

Improve lymphocyte ratio

Improve ovarian function through PPAR and cholesterol metabolism pathways

[80]

C57BL/6 (4–6 weeks)

CTX (70 mg/kg) + BF (12 mg/kg)

hUCMSCs (5 × 10⁵/mL) in 10 μL PBS

iv

Increase ovarian weight and follicle number,

Decrease FSH, increase AMH, FSHR;

Increase pregnancy rate

NO Report

[81]

Exosome from hUCMSCs

SD Rat (60–80 g)

CIS

(3 μg/ml)

huMSC-EXOs (20 µg, 100 µg/ml

–

Alleviate apoptosis level

Increase E2 level

NO Report

[82]

C57BL/6–(8 weeks)

CTX (120 mg/kg two times)

huMSC-EXOs (20 μg/mL, 150 μg)

Ip

Improve the pregnancy rate (Exo 83.33% vs POF 33.33%)

Increase FSHR

promoted ovarian cells proliferation

Promoted ovarian granulosa cell (OGCs) Proliferation In Vitro by Regulating the Hippo Pathway and the Effect Was Inhibited by a YAP Inhibitor

[72]

Wistar Rat (50–60 g)

CIS

(4 µg/ml)

huMSC-EXOs (30 µg/ml

–

promote resistance to apoptosis and protect OGCs from CIS-induced injury in vitro

huMSC-EXOs could be incorporated into injured OGCs, accelerating the recovery of OGCs

Exosomes carry a variety of microRNAs and proteins into target cells

[83]

Collagen/hUCMSCs

C57BL/6 (6 weeks)

CTX (40 mg/kg for 15 days)

Collagen/UCMSCs (2 × 10⁵/mL) in 10 μL PBS

Orthotopically inject

Increase E2 and AMH, decrease FSH level;

Promote the formation of granulomatous cell, ovarian angiogenesis

Promote ovarian angiogenesis with the increase of CD31 expression

[73]

Matrigel/hUCMSCs

C57BL/6 (8 weeks)

CTX

(1st , 100 mg/kg, 10 mg/kg for 14 days)

UCMSCs (5 × 10⁵/mL, passages 3–5) in 2.5 μL saline solution + 2.5 μL Matrigel

Orthotopically inject

Increase the number of follicles and decrease the rate of tissue fibro-degeneration;

Increase the proliferation rate of granuloma cells;

Increase the number of vascular radiosensitivity

Decrease the expression of TGFβ-1

Increase the expression of EGF, TGFβ-3 and VEGF-A

[84]

hESC-MSCs

C57BL/6 (6–8 weeks)

CTX (100 mg/kg) + BF (50 mg/kg)

hESC-MSCs (1 × 10⁶ cells)

iv

Promotes follicle development;

Decrease FSH, increase AMH, E2;

Restores fertility

Through paracrine VEGF, IGF-2 and HGF

[69]

ICR or C57BL/DBA

(7 weeks)

CIS

(2 mg/kg for 10 days)

hESC-MSCs (passage 8~10)

iv

Increase the mean number of primary and primordial follicles, decrease the count of residual zona pellucida (a marker of apoptosis in ovarian follicles),

Increase ovulation, embryo formation, and live birth rates

NO Report

[85]

hPMSCs

Balb/c

(6–8 weeks)

ZP3

hPMSCs (1 × 10⁶ cells, passages 6)

iv

Increased E2 level and decreased FSH and LH levels;

Increase follicles and decrease atretic follicles;

Inhibit OGCs apoptosis

By ER stress IRE1α signaling pathway

[27]

Balb/c

(7–8 weeks)

ZP3

hPMSCs (1 × 10⁶ cells, passages 6)

iv

Improve Estrous Cycles;

Inhibit Ovarian OGCs apoptosis;

Increase E2 and FSH Secretion

Increase CD25⁺CD4⁺Treg cell,

inflammatory regulations mediated by IFN-g and TGF-b

[28]

fMSCs

ICR

(7–8 weeks)

CTX (120 mg/kg for 2 weeks)

fMSCs (1 × 10⁶ cells)

iv

Increased E2 and AMH level and decreased FSH levels;

Increased sinus follicle number;

Inhibit apoptosis

Regulate MT1, JNK1, PCNA and AMPK to reduce the oxidative damage of POI cells, enhance the oxidative protection and improve their anti-apoptosis effect

[86]

ICR

(4–6 weeks)

CTX (200 mg/kg) + BF (20 mg/kg)

fMSCs (5 × 10⁵ cells) in 5μL PBS

Orthotopically inject

Reduced apoptosis;

Increase the number of primordial follicles and decrease the number of atretic follicles

Exosomal miR-10a derived from fMSCs protect the ovaries

[87]

hAMSCs

C57BL/6 (8 weeks)

Surgery (Hydrogen peroxide burns)

hAECs (1 × 10⁶ cells) in 300 μL PBS

Ip

Improve the estrous cycle;

Decreased FSH levels;

Increased the body weight and ovarian;

Enhance the fertility

Increase the number of primordial follicles and decrease the number of atretic follicles

Downregulate the expression of TNF-α and IL-1β

[88]

C57BL/6 (8 weeks)

CTX (50 mg/kg for 15 days)

hAECs (2 × 10⁶ cells) in 200 μL PBS

iv

Increased E2 level and decreased FSH level;

Increases the number of oocytes;

NO Report

[89]

Exosome from hAMSCs

C57BL/6 (10 week)

CTX (120 mg/kg for 2 weeks)

hAMSC-Exos (100 μL of PBS containing the 150 μg exosomes)

iv

Increased follicular numbers;

Enhanced the E2 and AMH levels and decreased the FSH levels;

Inhibit OGCs apoptosis

Inhibited the protein expression of SIRT4, ANT2, AMPK, and L-OPA1

[90]

hAECs

C57BL/6 (7–8 weeks)

CTX (120 mg/kg) + BF (30 mg/kg)

hAECs (12 × 10⁶ cells)

iv

Inhibition of chemotherapy-induced inflammation;

Inhibit Ovarian OGCs apoptosis;

Increase the number of cumulus oocyte complexes, increase secondary and mature follicles and decrease atretic follicles

Inhibit TNF-α-mediated cell apoptosis

[91]

C57BL/6 (7–8 weeks)

CTX (120 mg/kg) + BF (30 mg/kg)

hAECs (2 × 10⁴ cells) in 10 μL PBS

Orthotopically inject

Increase secondary and mature follicles and decrease atretic follicles;

Increase AMH, MVH, BMP15 and HAS2;

Inhibit the apoptosis of primary human granulosa-lutein (hGL) cells;

Promote angiogenesis and vasoformation

Activate TGF-β/Smad pathway in human luteinized OGCs

[92]

ICR mice (7–8 weeks)

CTX (70 mg/kg for 1 weeks  + 120 mg/kg for 1 weeks)

hAECs

Orthotopically inject

Increased E2 and AMH level and decreased FSH levels;

Increased ovary weight;

Increase secondary and mature follicles and decrease atretic follicles;

Increase fertilizing ability;

Increase the proliferation rate of OGCs

NO Report

[71]

Exosome from hAECs

Mice

(7–8 weeks)

CTX (120 mg/kg) + BF (30 mg/kg)

hAECs Exosome (1st : 9th, orthotopic injection, 10 μL) and 2nd: 10th, tail vein injection, 100 μL))

Orthotopic injection, iv

Inhibit OGCs apoptosis;

Protect the ovarian vasculature from damage;

Maintain the number of primordial follicles

Transfer functional miRNAs, such as miR-1246

[93]

SA-BG encapsulated hAECs

Mice

(8 weeks)

CTX (120 mg/kg) + BF (30 mg/kg)

hAECs (6 × 10⁷ cells) in 0.2 mL PBS + 2 mL SA-BG

Orthotopically inject

promoted the proliferation of granulomatous cells in antral follicles;

Enhanced angiogenesis;

Promoted the tube formation

Stimulated the secretion of pro-angiogenic factors

[74]