Exosomal miRNA-17-5p derived from human umbilical cord mesenchymal stem cells improves ovarian function in premature ovarian insufficiency by regulating SIRT7

Stem Cells ◽  
2020 ◽  
Author(s):  
Chenyue Ding ◽  
Liping Zhu ◽  
Han Shen ◽  
Jiafeng Lu ◽  
Qinyan Zou ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Umbilical Cord ◽  
Ovarian Function ◽  
Premature Ovarian Insufficiency ◽  
Human Umbilical Cord ◽  
Ovarian Insufficiency ◽  
Exosomal Mirna

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

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.

scholarly journals Effects of single transplantation and multiple transplantation of human umbilical cord mesenchymal stem cells on the recovery of ovarian function in the treatment of premature ovarian failure in mice

2021 ◽  
Author(s):  
Xiaodan Lv ◽  
Chunyi Guan ◽  
Ying Li ◽  
Xing Su ◽  
lu Zhang ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Real Time ◽  
Umbilical Cord ◽  
Premature Ovarian Failure ◽  
Real Time Pcr ◽  
Ovarian Function ◽  
Follicle Stimulating Hormone ◽  
Ovarian Failure ◽  
Human Umbilical Cord

Abstract BackgroundAt present, there is no effective treatment for premature ovarian failure (POF), and stem cell therapy is considered the most promising treatment. Human umbilical cord blood mesenchymal stem cells (hUC-MSCs) have shown good regenerative ability in a variety of diseases including POI, but the method and dosage of hUC-MSCs to treat POI are not clear. This study aims to explore the treatment options of hUC-MSCs for POF by comparing single injection and multiple injections of hUC-MSCs on the ovarian function repair of POF caused by chemotherapy drugs.MethodsFemale mice were injected intraperitoneally with 30 mg/kg of busulfan and 120 mg/kg of cyclophosphamide to induce POF. In the single hUC-MSCs injection group, 7 days after the mice were injected with cyclophosphamide and busulfan, hUC-MSCs were transplanted into these mice. In the multiple injection group, hUC-MSCs were transplanted 7 days, 14 days and 21 days after the mice were injected with cyclophosphamide and busulfan. We evaluated ovarian morphology, fertility, follicle stimulating hormone and estradiol concentration, and follicle count, evaluated POF model and cell transplantation. In addition, real-time PCR, immunohistochemistry, miRNA chip and mRNA chip are used to evaluate the effect of cell therapy.ResultsCompared with the POF group, the ovarian size and primordial follicle count in the hUC-MSC group were significantly improved, and the fertility was also significantly improved. Immunohistochemistry showed that compared with the POF group, the anti-Mullerian hormone and Ki-67 in the ovary of the hUC-MSC group increased significantly, and ovulation was significantly restored. Real-time PCR showed that the expression of follicle stimulating hormone receptor, inhibin and inhibin in the hUC-MSCs group was significantly restored compared with the POF group. The results of mRNA and miRNA chips also showed that hUC-MSC restored ovarian function at the gene level. long-term treatment effect shows that the multiple transplantation hUC-MSCs group is better than the single transplantation hUC-MSCs group. 60 days after the mice were injected with cyclophosphamide and busulfan, the organ coefficient of multiple transplantation of hUC-MSCs increased compared with the POF group, the number of primary follicles increased, and hormone secretion increased. ConclusionThe results show that multiple trasplantation of hUC-MSCs can promote the recovery of ovarian function in POF mice more than a single transplantation. This study provides a basis for the therapeutic dose and therapeutic effect of hUC-MSCs on POF.

scholarly journals Therapeutic Potential of HUMSCs in Female Reproductive Aging

2021 ◽  
Vol 9 ◽  
Author(s):  
Qiaojuan Mei ◽  
Hongbei Mou ◽  
Xuemei Liu ◽  
Wenpei Xiang
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Umbilical Cord ◽  
Ovarian Function ◽  
Therapeutic Potential ◽  
Human Umbilical Cord ◽  
Great Success ◽  
Reproductive Aging ◽  
Paracrine Factors ◽  
Paracrine Effects

With the development of regenerative medicine, stem cells are being considered more frequently for the treatment of reproductive aging. Human umbilical cord mesenchymal stem cells have been reported to improve the reserve function of aging ovaries through their homing and paracrine effects. In this process, paracrine factors secreted by stem cells play an important role in ovarian recovery. Although the transplantation of human umbilical cord mesenchymal stem cells to improve ovarian function has been studied with great success in animal models of reproductive aging, their application in clinical research and therapy is still relatively rare. Therefore, this paper reviews the role of human umbilical cord mesenchymal stem cells in the treatment of reproductive aging and their related mechanisms, and it does so in order to provide a theoretical basis for further research and clinical treatment.

scholarly journals Human Umbilical Cord Mesenchymal Stem Cells Therapy in Cyclophosphamide-Induced Premature Ovarian Failure Rat Model

2016 ◽  
Vol 2016 ◽  
pp. 1-13 ◽  
Author(s):  
Dan Song ◽  
Yun Zhong ◽  
Chunfeng Qian ◽  
Qinyan Zou ◽  
Jian Ou ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Umbilical Cord ◽  
Rat Model ◽  
Premature Ovarian Failure ◽  
Ovarian Function ◽  
Hormone Secretion ◽  
Ovarian Failure ◽  
Human Umbilical Cord ◽  
Ovarian Cells

Premature ovarian failure (POF) is one of the most common causes of infertility in women. In our present study, we established cyclophosphamide- (CTX-) induced POF rat model and elucidated its effect on ovarian function. We detected the serum estrogen, follicle stimulating hormone, and anti-Müllerian hormone of mice models by ELISA and evaluated their folliculogenesis by histopathology examination. Our study revealed that CTX administration could severely disturb hormone secretion and influence folliculogenesis in rat. This study also detected ovarian cells apoptosis by deoxy-UTP-digoxigenin nick end labeling (TUNEL) and demonstrated marked ovarian cells apoptosis in rat models following CTX administration. In order to explore the potential of human umbilical cord mesenchymal stem cells (UCMSCs) in POF treatment, the above indexes were used to evaluate ovarian function. We found that human UCMSCs transplantation recovered disturbed hormone secretion and folliculogenesis in POF rat, in addition to reduced ovarian cell apoptosis. We also tracked transplanted UCMSCs in ovaries by fluorescencein situhybridization (FISH). The results manifested that the transplanted human UCMSCs could reside in ovarian tissues and could survive for a comparatively long time without obvious proliferation. Our present study provides new insights into the great clinical potential of human UCMSCs in POF treatment.

scholarly journals The protective effects of human umbilical cord mesenchymal stem cells on damaged ovarian function: A comparative study

2016 ◽  
Vol 10 (4) ◽  
pp. 265-276 ◽  
Author(s):  
Jinjin Zhang ◽  
Jiaqiang Xiong ◽  
Li Fang ◽  
Zhiyong Lu ◽  
Meng Wu ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Comparative Study ◽  
Umbilical Cord ◽  
Ovarian Function ◽  
Human Umbilical Cord ◽  
Protective Effects

scholarly journals Effects of Single Transplantation and Multiple Transplantation of Human Umbilical Cord Mesenchymal Stem Cells on the Recovery of Ovarian Function in the Treatment of Premature Ovarian Failure in Mice

2020 ◽  
Author(s):  
Xiaodan Lv ◽  
Chunyi Guan ◽  
Ying Li ◽  
Xing Su ◽  
lu Zhang ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Umbilical Cord ◽  
Premature Ovarian Failure ◽  
Ovarian Function ◽  
Ovarian Tissue ◽  
Ovarian Failure ◽  
Mouse Serum ◽  
Enzyme Linked Immunosorbent Assay ◽  
Human Umbilical Cord

Abstract Background: Previous studies have reported that transplantation of mesenchymal stem cells (MSCs) from many human tissues can improve ovarian dysfunction. However, the therapeutic effects of single injection of MSCs and multiple injections of MSCs on premature ovarian failure (POF) have not been reported yet. In this study, we used long-term follow-up to study the effect of human umbilical cord mesenchymal stem cell (hUC-MSCs) on the functional recovery of mouse POF models. Methods: In this study, we used a mouse model of premature ovarian failure induced by the combination of 120mg/kg cyclophosphamide and 30mg/kg busulfan. Enzyme-linked immunosorbent assay (ELISA) was used to detect estradiol (E2) and follicle stimulating hormone (FSH) levels in mouse serum. Evaluate ovarian function by counting follicles, ovarian weight, number of proliferating cells, anti-Mullerian hormone (AMH) and oocytes. Results: Our study shows that hUC-MSCs have obvious therapeutic effect for the POF mice model, and treatment effect of multiple transplantation is better than single transplantation. Mesenchymal stem cells were detected in follicular granulosa cells with tracer of the ovarian tissue freezing slice, which show hUC-MSCs to selectively migration and stay in damaged tissues. Genome Array screened a number of differentially expressed genes, the hUC-MSCs can change the level of expression of certain genes in the ovarian tissue, thus affecting ovarian function, and laid the foundation for us to further explore the mechanism of hUC-MSCs treatment of premature ovarian failure. Conclusion: This study demonstrated that hUC-MSCs transplantation significantly restored ovarian function after chemotherapy-induced damage.

scholarly journals Human Umbilical Cord Mesenchymal Stem Cell-Derived Exosomes Improve Ovarian Function and Proliferation of Premature Ovarian Insufficiency by Regulating the Hippo Signaling Pathway

2021 ◽  
Vol 12 ◽  
Author(s):  
Zhongkang Li ◽  
Mingle Zhang ◽  
Jiahua Zheng ◽  
Yanpeng Tian ◽  
Huihui Zhang ◽  
...  
Keyword(s):  
Stem Cell ◽  
Mesenchymal Stem Cell ◽  
Umbilical Cord ◽  
Ovarian Function ◽  
Hippo Pathway ◽  
Premature Ovarian Insufficiency ◽  
Human Umbilical Cord ◽  
Ovarian Insufficiency

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.

scholarly journals Effects of single and multiple transplantations of human umbilical cord mesenchymal stem cells on the recovery of ovarian function in the treatment of premature ovarian failure in mice

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Xiaodan Lv ◽  
Chunyi Guan ◽  
Ying Li ◽  
Xing Su ◽  
Lu Zhang ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Cell Therapy ◽  
Umbilical Cord ◽  
Premature Ovarian Failure ◽  
Ovarian Function ◽  
Ovarian Failure ◽  
Human Umbilical Cord ◽  
Injection Group ◽  
Ovarian Morphology

Abstract Background Currently, there is no effective treatment for premature ovarian failure (POF), and stem cell therapy is considered the most promising treatment. Human umbilical cord blood mesenchymal stem cells (hUC-MSCs) have shown good regenerative ability in various diseases, including POF; however, their underlying mechanism and dosage for POF treatment remain unclear. This study aimed to compare the effect of single and multiple injections of hUC-MSCs on ovarian function repair in chemotherapy-induced POF. Methods Female mice were intraperitoneally injected with 30 mg/kg busulfan and 120 mg/kg cyclophosphamide (CTX) to induce POF. In the single hUC-MSC injection group, hUC-MSCs were transplanted into mice D7 after CTX and busulfan administration, while in the multiple injection group, hUC-MSCs were transplanted on D7, D14, and D21 after CTX and busulfan administration. We evaluated the ovarian morphology, fertility, follicle-stimulating hormone and estradiol concentrations, follicle count, POF model, and cell transplantation results. In addition, real-time polymerase chain reaction, immunohistochemistry, and miRNA and mRNA chips were used to evaluate the effect of the cell therapy. Results Ovary size, number of follicle at all developmental stages, and fertility were significantly reduced in the POF group compared with the control. Under hUC-MSC treatment, the ovarian morphology and follicle count were significantly restored, and fertility was significantly increased. By comparing the single and multiple hUC-MSC injection groups, we found that the anti-Müllerian hormone and Ki-67 levels were significantly increased in the multiple hUC-MSC group on D60 after chemotherapy. The expression of stimulating hormone receptors, inhibin α, and inhibin β was significantly restored, and the therapeutic effect was superior to that of the single hUC-MSC injection group. Conclusion These results indicate that hUC-MSCs can restore the structure of injured ovarian tissue and its function in chemotherapy-induced POF mice and ameliorate fertility. Multiple hUC-MSC transplantations have a better effect on the recovery of ovarian function than single hUC-MSC transplantation in POF.

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