PMID- 37777781 OWN - NLM STAT- MEDLINE DCOM- 20231013 LR - 20231121 IS - 1757-2215 (Electronic) IS - 1757-2215 (Linking) VI - 16 IP - 1 DP - 2023 Sep 30 TI - Human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) alleviate excessive autophagy of ovarian granular cells through VEGFA/PI3K/AKT/mTOR pathway in premature ovarian failure rat model. PG - 198 LID - 10.1186/s13048-023-01278-z [doi] LID - 198 AB - BACKGROUND: Premature ovarian failure (POF) is one of the leading causes of female infertility and is accompanied by abnormal endocrine, seriously affecting female quality of life. Previous studies have demonstrated that mesenchymal stem cells (MSCs) transplantation is a promising therapeutic strategy for POF. However, the mechanism remains obscure. This study aims to investigate the therapeutic effect of human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) on ovarian function in the POF rat model and explore the underlying mechanisms. METHODS: The ovarian function was evaluated by ovarian morphology, histology, estrous cycle, hormone levels (AMH, E2, FSH, and LH), and fertility ability to investigate the effect of hUC-MSCs on the POF rats model. The cytokines levels were assayed in serum using protein array to explore the mechanisms of hUC-MSCs therapy for POF. The excessive autophagy levels were evaluated using a co-culture system of 3D MSCs spheroids with human ovarian granulosa cell line (KGN) or primary ovarian granulosa cells (GCs) to understand the paracrine effect of hUC-MSCs on GCs. The related proteins expression of autophagy and PI3K/AKT/mTOR pathway was detected using Western Blotting and/or in various inhibitors supplement to further demonstrate that vascular endothelial growth factor A (VEGFA) secreted by hUC-MSCs can alleviate excessive autophagy of ovarian GCs via PI3K/AKT/mTOR signaling pathway. The ovarian culture model in vitro was applied to confirm the mechanism. RESULTS: The ovarian function of POF and the excessive autophagy of ovarian GCs were restored after hUC-MSCs transplantation. The protein array result demonstrated that VEGF and PI3K/AKT might improve ovarian function. in vitro experiments demonstrated that VEGFA secreted by hUC-MSCs could decrease oxidative stress and inhibit excessive autophagy of ovarian GCs via PI3K/AKT/mTOR pathway. The ovarian culture model results confirmed this mechanism in vitro. CONCLUSION: The hUC-MSCs can alleviate excessive autophagy of ovarian GCs via paracrine VEGFA and regulate the PI3K/AKT/mTOR signaling pathway, thereby improving the ovarian function of POF. CI - (c) 2023. BioMed Central Ltd., part of Springer Nature. FAU - Dai, Wenjie AU - Dai W AD - Key Laboratory of Fertility Preservation and Maintenance of Ministry of Education, School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, 750004, China. FAU - Yang, Hong AU - Yang H AD - Key Laboratory of Fertility Preservation and Maintenance of Ministry of Education, School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, 750004, China. FAU - Xu, Bo AU - Xu B AD - Key Laboratory of Fertility Preservation and Maintenance of Ministry of Education, School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, 750004, China. FAU - He, Tiantian AU - He T AD - Key Laboratory of Fertility Preservation and Maintenance of Ministry of Education, School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, 750004, China. FAU - Liu, Ling AU - Liu L AD - Key Laboratory of Fertility Preservation and Maintenance of Ministry of Education, School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, 750004, China. FAU - Ma, Xiaoqian AU - Ma X AD - Key Laboratory of Fertility Preservation and Maintenance of Ministry of Education, School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, 750004, China. FAU - Ma, Jiaxue AU - Ma J AD - Key Laboratory of Fertility Preservation and Maintenance of Ministry of Education, School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, 750004, China. FAU - Yang, Guoqin AU - Yang G AD - Key Laboratory of Fertility Preservation and Maintenance of Ministry of Education, School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, 750004, China. FAU - Si, Rui AU - Si R AD - Key Laboratory of Fertility Preservation and Maintenance of Ministry of Education, School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, 750004, China. FAU - Pei, Xiuying AU - Pei X AD - Key Laboratory of Fertility Preservation and Maintenance of Ministry of Education, School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, 750004, China. FAU - Du, Xing AU - Du X AD - Key Laboratory of Fertility Preservation and Maintenance of Ministry of Education, School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, 750004, China. duxingok@126.com. FAU - Fu, Xufeng AU - Fu X AD - Key Laboratory of Fertility Preservation and Maintenance of Ministry of Education, School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, 750004, China. fuxufeng100@163.com. LA - eng GR - 81960270/National Natural Science Foundation of China/ PT - Journal Article DEP - 20230930 PL - England TA - J Ovarian Res JT - Journal of ovarian research JID - 101474849 RN - EC 2.7.1.1 (mTOR protein, rat) RN - EC 2.7.1.- (Phosphatidylinositol 3-Kinases) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - 0 (Vascular Endothelial Growth Factor A) RN - 0 (VEGFA protein, human) SB - IM MH - Animals MH - Female MH - Humans MH - Rats MH - Autophagy MH - *Mesenchymal Stem Cell Transplantation MH - *Mesenchymal Stem Cells/metabolism MH - Phosphatidylinositol 3-Kinases/metabolism MH - *Primary Ovarian Insufficiency/therapy MH - Proto-Oncogene Proteins c-akt/metabolism MH - Quality of Life MH - TOR Serine-Threonine Kinases/metabolism MH - Umbilical Cord MH - Vascular Endothelial Growth Factor A/metabolism PMC - PMC10542694 OTO - NOTNLM OT - Excessive autophagy OT - Human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) OT - Ovarian granulosa cells OT - PI3K/AKT/mTOR OT - Premature ovarian failure COIS- The authors declare no competing interests. EDAT- 2023/10/01 04:44 MHDA- 2023/10/05 06:44 PMCR- 2023/09/30 CRDT- 2023/09/30 23:36 PHST- 2023/06/11 00:00 [received] PHST- 2023/09/12 00:00 [accepted] PHST- 2023/10/05 06:44 [medline] PHST- 2023/10/01 04:44 [pubmed] PHST- 2023/09/30 23:36 [entrez] PHST- 2023/09/30 00:00 [pmc-release] AID - 10.1186/s13048-023-01278-z [pii] AID - 1278 [pii] AID - 10.1186/s13048-023-01278-z [doi] PST - epublish SO - J Ovarian Res. 2023 Sep 30;16(1):198. doi: 10.1186/s13048-023-01278-z.