Human amnion-derived mesenchymal stem cell (hAD-MSC) transplantation improves ovarian function in rats with premature ovarian insufficiency (POI) at least partly through a paracrine mechanism

BackgroundPremature ovarian insufficiency (POI) is associated with severe physical damage and psychological burden on women. Transplantation of exosomes is an encouraging regenerative medicine method, which has the potential for restoring ovarian functions on POI with high efficiency. This study aims at evaluating the therapeutic efficacy of human umbilical cord mesenchymal stem cell-derived exosomes (hUCMSC-Exos) on ovarian dysfunction of POI and the role of Hippo pathway in this exosome-mediated treatment.MethodsPOI mice models were established through intraperitoneal injection of cyclophosphamide. Subsequently, transplantation of hUCMSC-Exos was conducted to administer POI mice. Ovaries and plasma of these mice models were harvested after two weeks of treatment. Ovarian morphology and follicle number were assessed by hematoxylin and eosin staining. Moreover, ELISA was used to detect hormone levels, which are related to ovarian function in serum. To assess the recovery of reproductive ability, we recorded the rate of pregnancy, the amount of offspring, and the time of birth in different groups. To explore the underlying mechanisms of exosome-mediated treatment for ovarian function recovery, the proliferation of ovarian cells in vivo was detected by immunohistochemistry and immunofluorescence staining. Additionally, we conducted EdU and CCK-8 assays to assess the proliferative ability of ovarian granulosa cells (GCs) that were cultured in vitro. Western blot analysis was conducted to estimate the proteins levels of Hippo- and proliferation-associated molecules in vivo and in vitro.ResultsAfter transplantation of hUCMSC-Exos, the ovarian function-related hormone levels and the number of ovarian follicles returned to nearly normal degrees. Meanwhile, there was a significant improvement in reproductive outcomes after exosomal treatment. Furthermore, the improvement of ovarian function and proliferation was associated with the regulation of Hippo pathway. In vitro, co-culture with exosomes significantly elevated the proliferation of ovarian GCs by regulating Hippo pathway. However, the positive effects on the proliferation of GCs were significantly depressed when key Hippo pathway molecule was inhibited.ConclusionThis study suggested that hUCMSC-Exos promoted ovarian functions and proliferation by regulating the Hippo pathway. Therefore, exosomal transplantation could be a promising and efficient clinical therapy for POI in the near future.

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Adipose-Derived Mesenchymal Stem Cell Transplantation in Chemotherapy-Induced Premature Ovarian Insufficiency: the Role of Connexin and Pannexin

Reproductive Sciences ◽

10.1007/s43032-021-00718-9 ◽

2021 ◽

Author(s):

Busra Sen Halicioglu ◽

Khandakar A. S. M. Saadat ◽

Mehmet Ibrahim Tuglu

Keyword(s):

Stem Cell ◽

Mesenchymal Stem Cell ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Premature Ovarian Insufficiency ◽

Ovarian Insufficiency ◽

Mesenchymal Stem Cell Transplantation

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Effects of low-intensity pulsed ultrasound (LIPUS)-pretreated human amnion-derived mesenchymal stem cell (hAD-MSC) transplantation on primary ovarian insufficiency in rats

Stem Cell Research & Therapy ◽

10.1186/s13287-017-0739-3 ◽

2017 ◽

Vol 8 (1) ◽

Cited By ~ 12

Author(s):

Li Ling ◽

Xiushan Feng ◽

Tianqin Wei ◽

Yan Wang ◽

Yaping Wang ◽

...

Keyword(s):

Stem Cell ◽

Mesenchymal Stem Cell ◽

Primary Ovarian Insufficiency ◽

Pulsed Ultrasound ◽

Ovarian Insufficiency ◽

Human Amnion ◽

Low Intensity Pulsed Ultrasound ◽

Low Intensity

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Premature ovarian insufficiency: pathogenesis and therapeutic potential of mesenchymal stem cell

Journal of Molecular Medicine ◽

10.1007/s00109-021-02055-5 ◽

2021 ◽

Vol 99 (5) ◽

pp. 637-650

Author(s):

Akimasa Takahashi ◽

Abdelrahman Yousif ◽

Linda Hong ◽

IIana Chefetz

Keyword(s):

Stem Cell ◽

Mesenchymal Stem Cell ◽

Therapeutic Potential ◽

Premature Ovarian Insufficiency ◽

Ovarian Insufficiency

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Human umbilical cord mesenchymal stem cells restore the ovarian metabolome and rescue premature ovarian insufficiency in mice

Stem Cell Research & Therapy ◽

10.1186/s13287-020-01972-5 ◽

2020 ◽

Vol 11 (1) ◽

Author(s):

Yan Zhao ◽

Jiao Ma ◽

Peiye Yi ◽

Jun Wu ◽

Feiyan Zhao ◽

...

Keyword(s):

Amino Acids ◽

Stem Cells ◽

Mesenchymal Stem Cells ◽

Stem Cell ◽

Umbilical Cord ◽

Ovarian Function ◽

Premature Ovarian Insufficiency ◽

Reproductive Capacity ◽

Human Umbilical Cord ◽

Ovarian Insufficiency

Abstract 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.

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