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

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.

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

“…By generating a multifunctional secretome, MSCs can stimulate proliferation, inhibit apoptosis, and improve the microenvironment in the ovary [ 14 , 15 ]. The finely balanced phosphatidylinositol 3 kinase (PI3K)-protein kinase B (AKT) pathway in the mammalian ovary is essential for folliculogenesis, and insufficient activation of this pathway will impair the survival of primordial follicles leading to POI [ 16 , 17 ].…”

A comparative study of Mesenchymal Stem Cells transplantation approach to antagonize age-associated ovarian hypofunction with consideration of safety and efficiency

“…Mice of 32 weeks-old were randomly divided into three equal groups: Oc + BMSCs group (ovarian local injection), Ti + BMSCs group (tail-intravenous injection) and Intra-P + BMSCs group (intraperitoneal injection), all the above were injected with normal saline (NS) as control groups. As previously described [28] , [29] , all of the mice were appropriately transplanted with a concentration of 1.2 × 10 7 /ml MSCs (6 × 10 5 MSCs in 50 μl normal saline) by intraperitoneal, intravenous or ovarian local injections, respectively.…”

Mesenchymal Stem/Stromal Cells and Hydrogel Scaffolds for Tissue Engineering

“…As to premature ovarian insufficiency (POI), an intractable endocrine disease that severely restricts the reproductive and physiological function of females and resultant in menopausal symptoms, a series of literatures have suggested the ameliorative effect of hydrogel/MSC composite or hydrogel/MSC-derived microvesicles/secretomes via facilitating angiogenesis, enhancing granulosa cell generation and steroidogenesis, and accelerating follicular regeneration [98][99][100][101]. Notably, Li et al have summarized the current renewal of the therapeutic effects and molecular mechanisms of MSCbased cytotherapy in both preclinical research and clinical trials [102].…”