PMID- 33148334 OWN - NLM STAT- MEDLINE DCOM- 20210618 LR - 20210618 IS - 1757-6512 (Electronic) IS - 1757-6512 (Linking) VI - 11 IP - 1 DP - 2020 Nov 4 TI - Human umbilical cord mesenchymal stem cells restore the ovarian metabolome and rescue premature ovarian insufficiency in mice. PG - 466 LID - 10.1186/s13287-020-01972-5 [doi] LID - 466 AB - BACKGROUND: Premature ovarian insufficiency (POI) is an ovarian dysfunction that seriously affects a woman's physiological health and reproduction. Mesenchymal stem cell (MSC) transplantation offers a promising treatment option for ovarian restoration in rodent POI models. However, the efficacy and mechanism of it remain unclear. METHODS: POI mice model was generated by cyclophosphamide and busulfan, followed with the treatment of tail-vein injection of the human umbilical cord mesenchymal stem cells (hUCMSCs). Maternal physiological changes and offspring behavior were detected. To reveal the pathogenesis and therapeutic mechanisms of POI, we first compared the metabolite profiles of healthy and POI ovarian tissues using untargeted metabolomics analyses. After stem cell therapy, we then collected the ovaries from control, POI, and hUCMSC-treated POI groups for lipid metabolomics and pseudotargeted metabolomics analysis. RESULTS: Our results revealed remarkable changes of multiple metabolites, especially lipids, in ovarian tissues after POI generation. Following the transplantation of clinical-grade hUCMSCs, POI mice exhibited significant improvements in body weight, sex hormone levels, estrous cycles, and reproductive capacity. Lipid metabolomics and pseudotargeted metabolomics analyses for the ovaries showed that the metabolite levels in the POI group, mainly lipids, glycerophospholipids, steroids, and amino acids changed significantly compared with the controls', and most of them returned to near-healthy levels after receiving hUCMSC treatment. Meanwhile, we also observed an increase of monosaccharide levels in the ovaries from POI mice and a decrease after stem cell treatment. CONCLUSIONS: hUCMSCs restore ovarian function through activating the PI3K pathway by promoting the level of free amino acids, consequently improving lipid metabolism and reducing the concentration of monosaccharides. These findings provide potential targets for the clinical diagnosis and treatment of POI. FAU - Zhao, Yan AU - Zhao Y AD - State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China. AD - University of Chinese Academy of Sciences, Beijing, 100049, China. AD - Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China. FAU - Ma, Jiao AU - Ma J AD - State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China. AD - University of Chinese Academy of Sciences, Beijing, 100049, China. AD - Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China. FAU - Yi, Peiye AU - Yi P AD - State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China. AD - University of Chinese Academy of Sciences, Beijing, 100049, China. AD - Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China. FAU - Wu, Jun AU - Wu J AD - State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China. AD - Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China. AD - National Stem Cell Resource Center, Chinese Academy of Sciences, Beijing, 100101, China. FAU - Zhao, Feiyan AU - Zhao F AD - Department of Human Reproductive Medicine, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, 100026, China. FAU - Tu, Wan AU - Tu W AD - State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China. AD - University of Chinese Academy of Sciences, Beijing, 100049, China. AD - Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China. FAU - Liu, Wenjing AU - Liu W AD - Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China. AD - National Stem Cell Resource Center, Chinese Academy of Sciences, Beijing, 100101, China. FAU - Li, Tianda AU - Li T AD - State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China. AD - Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China. FAU - Deng, Yan AU - Deng Y AD - National Stem Cell Resource Center, Chinese Academy of Sciences, Beijing, 100101, China. FAU - Hao, Jie AU - Hao J AD - State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China. haojie@ioz.ac.cn. AD - Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China. haojie@ioz.ac.cn. AD - National Stem Cell Resource Center, Chinese Academy of Sciences, Beijing, 100101, China. haojie@ioz.ac.cn. FAU - Wang, Hongmei AU - Wang H AD - State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China. wanghm@ioz.ac.cn. AD - University of Chinese Academy of Sciences, Beijing, 100049, China. wanghm@ioz.ac.cn. AD - Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China. wanghm@ioz.ac.cn. FAU - Yan, Long AU - Yan L AUID- ORCID: 0000-0001-9274-7950 AD - State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China. yanlong@ioz.ac.cn. AD - University of Chinese Academy of Sciences, Beijing, 100049, China. yanlong@ioz.ac.cn. AD - Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China. yanlong@ioz.ac.cn. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20201104 PL - England TA - Stem Cell Res Ther JT - Stem cell research & therapy JID - 101527581 SB - IM MH - Animals MH - Female MH - Humans MH - *Mesenchymal Stem Cells MH - Metabolome MH - Mice MH - Ovary/metabolism MH - Phosphatidylinositol 3-Kinases/metabolism MH - *Primary Ovarian Insufficiency/metabolism/therapy MH - Umbilical Cord PMC - PMC7641864 OTO - NOTNLM OT - Mesenchymal stem cell OT - Metabolite OT - Metabolomics OT - Ovarian function restoration OT - Premature ovarian insufficiency COIS- The authors declare that they have no competing interests. EDAT- 2020/11/06 06:00 MHDA- 2021/06/22 06:00 PMCR- 2020/11/04 CRDT- 2020/11/05 05:37 PHST- 2020/08/27 00:00 [received] PHST- 2020/10/11 00:00 [accepted] PHST- 2020/11/05 05:37 [entrez] PHST- 2020/11/06 06:00 [pubmed] PHST- 2021/06/22 06:00 [medline] PHST- 2020/11/04 00:00 [pmc-release] AID - 10.1186/s13287-020-01972-5 [pii] AID - 1972 [pii] AID - 10.1186/s13287-020-01972-5 [doi] PST - epublish SO - Stem Cell Res Ther. 2020 Nov 4;11(1):466. doi: 10.1186/s13287-020-01972-5.