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Effects of Human Amnion–Derived Mesenchymal Stem Cell (hAD-MSC) Transplantation In Situ on Primary Ovarian Insufficiency in SD Rats

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Abstract

Human amnion–derived mesenchymal stem cell (hAD-MSC) transplantation can repair ovarian injury and improve ovarian function in rats with chemotherapy-induced primary ovarian insufficiency (POI). However, ensuring that stem cells home to the ovary to improve their effects on ovarian injury is challenging. This research aimed to directly inject ovarian tissue with hAD-MSCs and improve the homing of stem cells to the ovary. The animals were divided into POI, hAD-MSC (tail vein) treatment, hAD-MSC (in situ) treatment, and control groups. POI rat models were established by intraperitoneal injection of cyclophosphamide (CTX) and busulfan (BUS). The hAD-MSCs isolated from the amnion were injected into the tail vein or ovary of POI rats. The estrous cycle, serum sex hormone levels, follicle counts, ovarian pathological changes, and proteome of the ovaries were evaluated. hAD-MSCs were successfully isolated and cultured from the amnion. Both hAD-MSC (tail vein) and hAD-MSC (in situ) transplantation increased body weight, improved the AMH levels and follicle numbers, and reduced reproductive organ injuries in POI rats. Transplantation of hAD-MSCs (in situ) upregulated 24 proteins and downregulated 4 proteins. Both hAD-MSC (tail vein) and hAD-MSC (in situ) transplantations can repair ovarian injury and improve ovarian function in rats with chemotherapy-induced POI. The paracrine proteome of hAD-MSCs in the ovarian microenvironment can protect against chemotherapy-induced damage by reducing apoptosis and promoting angiogenesis, cell proliferation, and gene expression.

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Data Availability

The datasets used and/or analyzed during the current study are available from the corresponding author on a reasonable request.

Abbreviations

POI:

primary ovarian insufficiency

CTX:

cyclophosphamide

BUS:

busulfan

CTX:

cyclophosphamide

DAPI:

2-(4-amidinophenyl)-6-indolecarbamidine dihydrochloride

EDTA:

ethylenediaminetetraacetic acid

ELISA:

enzyme-linked immunosorbent assay

FGF:

fibroblast growth factor

FSH:

follicle-stimulating hormone

GC:

granulosa cell

H&E:

hematoxylin and eosin

hAD-MSC:

human amnion–derived mesenchymal stem cell

IGF:

insulin-like growth factor

IL:

interleukin

MSC:

mesenchymal stem cell

OCT:

optimal cutting temperature

POF:

premature ovarian failure

POI:

primary ovarian insufficiency

SD:

Sprague-Dawley

VEGF:

vascular endothelial growth factor

FBS:

fetal bovine serum

E2:

estradiol

ANOVA:

analysis of variance

ERK:

extracellular signal–regulated kinase

JNK:

c-Jun N-terminal kinase

Akt:

protein kinase B

PI3K:

phosphatidylinositol-3-kinase

MKK:

MAPK kinase

PF4:

platelet factor 4

MAPK:

mitogen-activated protein kinase

TNF:

tumor necrosis factor

MMP:

matrix metalloproteinase

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Funding

This study was supported by the National Natural Science Foundation of China (81671415).

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Authors and Affiliations

  1. Department of Obstetrics and Gynecology, the Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, China

    Xiushan Feng, Li Ling, Wenqian Zhang, Xiaohan Liu, Yanjing Luo & Zhengai Xiong

  2. Department of Obstetrics and Gynecology, Union Affiliated Hospital of Fujian Medical University, Fuzhou, 300010, China

    Xiushan Feng

  3. Department of Histology and Embryology, Laboratory of Stem Cell and Tissue Engineering, Chongqing Medical University, Chongqing, 400010, China

    Yaping Wang

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  1. Xiushan Feng
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Contributions

Conceived and designed the experiments: XF and ZX; literature search: XF and LL; performed the experiments: XF, LL, WZ, XL, YL, and DT; analyzed the data: XF and LL; helped perform the analysis with constructive discussions: XF, LL, YW, and ZX; drafted the manuscript: XF and LL. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Zhengai Xiong.

Ethics declarations

This research was in accordance with the Helsinki Declaration and approved by the Ethics Committee of the Second Affiliated Hospital of Chongqing Medical University.

Competing Interests

The authors declared that they have no conflict of interest.

Ethics Approval and Consent to Participate

The protocol was approved by the Committee on the Ethics of Animal Experiments of Chongqing Medical University (Permit Number: 2016-044).

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Feng, X., Ling, L., Zhang, W. et al. Effects of Human Amnion–Derived Mesenchymal Stem Cell (hAD-MSC) Transplantation In Situ on Primary Ovarian Insufficiency in SD Rats. Reprod. Sci. 27, 1502–1512 (2020). https://doi.org/10.1007/s43032-020-00147-0

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  • DOI: https://doi.org/10.1007/s43032-020-00147-0

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