NDLI: Mesenchymal stem cells combined with autocrosslinked hyaluronic acid improve mouse ovarian function by activating the PI3K-AKT pathway in a paracrine manner

Content Provider	Springer Nature : BioMed Central
Author	Jiao, Wenlin Mi, Xin Yang, Yajuan Liu, Ran Liu, Qiang Yan, Tao Chen, Zi-Jiang Qin, Yingying Zhao, Shidou
Abstract	Background Declining ovarian function in advance-aged women and in premature ovarian insufficiency (POI) patients seriously affects quality of life, and there is currently no effective treatment to rescue ovarian function in clinic. Stem cell transplantation is a promising therapeutic strategy for ovarian aging, but its clinical application is limited due to the low efficiency and unclear mechanism. Here, a novel combination of umbilical cord-mesenchymal stem cells (UC-MSCs) and autocrosslinked hyaluronic acid (HA) gel is explored to rescue ovarian reserve and fecundity in POI and naturally aging mice. Methods To investigate HA prolonged the survival after UC-MSCs transplantation, PCR and immunofluorescence were performed to track the cells on day 1, 3, 7 and 14 after transplantation. The effects of HA on UC-MSCs were analyzed by CCK8 assay, RNA-sequencing and 440 cytokine array. In vivo experiments were conducted to evaluate the therapeutic effects of UC-MSCs combined with HA transplantation in 4-vinylcyclohexene diepoxide (VCD)-induced POI mice and naturally aging mice model. Ovarian function was analyzed by ovarian morphology, follicle counts, estrous cycle, hormone levels and fertility ability. To investigate the mechanisms of stem cell therapy, conditioned medium was collected from UC-MSCs and fibroblast. Both in vitro ovarian culture model and 440 cytokine array were applied to assess the paracrine effect and determine the underlying mechanism. Hepatocyte growth factor (HGF) was identified as an effective factor and verified by HGF cytokine/neutralization antibody supplementation into ovarian culture system. Results HA not only prolongs the retention of UC-MSCs in the ovary, but also boosts their secretory function, and UC-MSCs promote follicular survival by activating the PI3K-AKT pathway through a paracrine mechanism both in vitro and in vivo. More importantly, HGF is identified as the key functional cytokine secreted by MSCs. Conclusions The results show that HA is an excellent cell scaffold to improve the treatment efficiency of UC-MSCs for ovarian aging under both physiological and pathological conditions, and the therapeutic mechanism is through activation of the PI3K-AKT pathway via HGF. These findings will facilitate the clinical application of MSCs transplantation for ovarian disorders.
Related Links	https://stemcellres.biomedcentral.com/counter/pdf/10.1186/s13287-022-02724-3.pdf
Ending Page	17
Page Count	17
Starting Page	1
File Format	HTM / HTML
ISSN	17576512
DOI	10.1186/s13287-022-02724-3
Journal	Stem Cell Research & Therapy
Issue Number	1
Volume Number	13
Language	English
Publisher	BioMed Central
Publisher Date	2022-02-02
Access Restriction	Open
Subject Keyword	Stem Cells Cell Biology Regenerative Medicine Tissue Engineering Biomedical Engineering and Bioengineering Mesenchymal stem cells Hyaluronic acid Paracrine PI3K-AKT pathway Premature ovarian insufficiency Ovarian aging Hepatocyte growth factor Regenerative Medicine/Tissue Engineering
Content Type	Text
Resource Type	Article
Subject	Cell Biology Medicine Biochemistry, Genetics and Molecular Biology Molecular Medicine
Journal Impact Factor	7.1/2023
5-Year Journal Impact Factor	7.9/2023

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