Stem Cell Paracrine Signaling for Treatment of Premature Ovarian Insufficiency

Polonio, Alba M.; García-Velasco, Juan A.; Herraiz, Sonia

doi:10.3389/fendo.2020.626322

Cited by 18 publications

(15 citation statements)

References 132 publications

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“…Importantly, for the first time, we found that CEFFE could repair the function of aged granulosa cells. Our previous studies have shown that CEFFE is rich in various growth factors, such as PDGF, BDNF, GDNF, and TGFβ, which are also abundant in the follicular fluid, contributing to the regulation of intrafollicular microenvironment and the maturation of granulosa cells and follicles ( 15 ). In contrast, PDGF and GDNF contents in the follicular fluid of patients with ovarian dysfunction (such as DOR and aging) were lower than those in young people with normal ovarian functions ( 42 ).…”

Section: Discussionmentioning

confidence: 99%

“…However, immune rejection and ethical risks of stem cell therapy and the limited source, low productivity, and difficulty in scaling up the production of exosomes have limited the clinical application of stem cells and exosomes ( 12 , 13 ). Several studies have shown that stem cells can contribute to tissue repair via secretion of growth factors ( 14 , 15 ). For example, adipose-derived stem cells can rescue the ovarian function via secretion of HGF and bFGF from stem cells ( 16 , 17 ).…”

Section: Introductionmentioning

confidence: 99%

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Cell-Free Fat Extract Improves Ovarian Function and Fertility in Mice With Advanced Age

Liu

Zhou

et al. 2022

Front. Endocrinol.

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The reduction in the quantity and quality of oocytes is the major factor affecting fertility in women with advanced age, who tend to experience delayed childbearing and declined fertility rate. However, effective therapeutic strategies to combat this decrease in ovarian function are lacking in clinical practice. Thus, identifying a new method to rescue ovarian function and improve reproduction in natural age-related decline in fertility is necessary. Cell-free fat extract (CEFFE) has been verified to possess diverse active proteins exerting anti-aging and proliferation-promoting effects. Nonetheless, whether CEFFE can rescue the decline in aged-related ovarian function and improve the fertility of females with advanced age remains unclear. In this study, a natural aging mouse model, exhibiting similarities to the physiological changes of ovarian senescence, was used to observe the anti-aging effect of CEFFE on ovarian functions. We found that CEFFE, injected via the veins, could recover the levels of the sex hormone, increase angiogenesis and the number of growth follicles in the natural aging mice model. Moreover, CEFFE promoted the development of embryos and increased the litter size of aged mice. Transcriptome analysis of the aged mouse ovaries revealed that CEFFE treatment upregulated the expression of genes involved in the repair of DNA damage. And both in vivo and in vitro experiment proved that CEFFE improved the function of granulosa cells, including promoting proliferation, alleviating senescence, and rescuing DNA damage in aged granulosa cells. Collectively, our study implied that CEFFE improved the ovarian function and fertility of naturally aging mice by ameliorating the overall microenvironment of ovary, which provided a theoretical basis for new anti-aging therapeutic strategies for cell-free therapy in ovaries.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Cell-Free Fat Extract Improves Ovarian Function and Fertility in Mice With Advanced Age

Liu

Zhou

et al. 2022

Front. Endocrinol.

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“…But long-term HRT also has certain risks, such as the occurrence of endometrial cancer and breast cancer [1] . Mesenchymal stem cell transplantation is considered to be a very promising treatment strategy for reversing the negative effects of POI [4]. One of the key events that contribute to ovarian aging includes follicular atresia as it is associated with the pyroptosis and necrosis of granulosa cells and thecal cells in aging ovaries.…”

Section: Discussionmentioning

confidence: 99%

Placental mesenchymal stem cells ameliorate NLRP3 inflammasome induced ovarian insufficiency by modulating macrophage M2 polarization

Chen

Xing

et al. 2022

Preprint

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Background: Premature ovarian insufficiency (POI) is a common clinical problem but there are currently no effective therapies. Pyroptosis induced by the NLRP3 inflammasome is considered a possible mechanism of POI. Placental mesenchymal stem cells(PMSCs) have excellent immunomodulatory potential and offer a promising method for treating POI. Methods: Female Sprague–Dawley rats were randomly divided into four treatment groups: control (no POI), POI with no PMSCs, POI with PMSCs transplant, and POI with hormones (estrogen+progesterone) as positive control. POI was induced by exposure to 4-vinylcyclohexene diepoxide (VCD) for 15 days. After four weeks, all animals were euthanized and examined for pathology. Hormone levels were measured and ovarian function was evaluated in relation to the estrous cycle. Levels of NLRP3 inflammasome pathway proteins were determined by immunohistochemistry and western blot. Results: VCD significantly damaged rat follicles at different estrous stages. Injection of human PMSCs improved ovarian function and reproductive ability of POI rats compared to the sham and hormone groups. Our data also showed that PMSCs could remarkably suppress cell pyroptosis via downregulation of the NLRP3 inflammasome, caspase-1, IL-1β and IL-18 compared to the other two groups. The human PMSCs increased the expression of IL-4 and IL-10 and decreased pro-inflammatory factors by phenotypic changes in macrophages. Conclusions: Our findings revealed a novel mechanism of follicular dysfunction and ovarian fibrosis via activation of the NLRP3 inflammasome followed by secretion of pro-inflammatory factors. Transplantation of PMSCs into POI rats suppressed pro-inflammatory factor production, NLRP3 inflammasome formation and pyroptosis, and improved ovarian function.

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“…In the past ten years, mounting evidences have indicated the beneficial application of mesenchymal stem cells (MSCs) on the treatment of POF. Studies have noted that the transplanted MSCs exert their therapeutic effects mainly through the paracrine mechanism instead of direct cell replacement [ 2 ], and the MSCs can be used to treat POF mainly owing to its effects on OGC apoptosis [ 3 ]. However, there are certain limitations to the clinical application of MSCs, such as potential immunogenicity or tumorigenicity [ 4 ].…”

Section: Introductionmentioning

confidence: 99%

miR-126-3p containing exosomes derived from human umbilical cord mesenchymal stem cells promote angiogenesis and attenuate ovarian granulosa cell apoptosis in a preclinical rat model of premature ovarian failure

LIU

Cui

et al. 2022

Stem Cell Res Ther

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Background In our previous research, we found that overexpression of miR-126-3p in human umbilical cord MSCs (hucMSCs) promoted human umbilical vein endothelial cells angiogenic activities through exosome-mediated mechanisms. The present study aimed to investigate the role of miR-126-3p-modified hucMSCs derived exosomes (miR-126-3p-hucMSCs-exosomes) on the treatment of premature ovarian failure (POF). Methods Primary hucMSCs were isolated from human umbilical cords and identified by differentiation experiments and flow cytometry. miR-126-3p-hucMSCs were obtained by miR-126-3p lentivirus infection. miR-126-3p-hucMSCs-exosomes were purified by ultracentrifugation method and characterized by transmission electron microscopy and western blot analysis. Primary rat ovarian granulosa cells (OGCs) were collected from ovarian tissues and identified by cell immunohistochemistry. The effects of miR-126-3p-hucMSCs-exosomes and miR-126-3p on OGCs function were determined by cell proliferation and apoptosis assays in a cisplatin induced POF cell model. The levels of suitable target genes were analyzed by PCR and Western blot analysis and subsequent Dual-Luciferase reporter assay. The signal pathway was also analyzed by western blot analysis. A cisplatin-induced POF rat model was used to validate the therapeutic effects of miR-126-3p-hucMSCs-exosomes to treat POF. Ovarian function was evaluated by physical, enzyme-linked immunosorbent assay, and histological examinations in chemotherapy-treated rats. The angiogenesis and apoptosis of ovarian tissues were assessed by immunohistochemical staining and Western blots. Results Primary hucMSCs and miR-126-3p-hucMSCs-exosomes and primary rat OGCs were successfully isolated and identified. The cellular uptake experiments indicated that miR-126-3p-hucMSC-exosomes can be internalized into OGCs in vitro. Annexin V-FITC/PI staining and EDU assays revealed that both miR-126-3p-hucMSCs-exosomes and miR-126-3p promoted proliferation and inhibited apoptosis of OGCs damaged by cisplatin. PCR and western blot analysis and subsequent dual-luciferase reporter assay verified that miR-126-3p targets the sequence in the 3' untranslated region of PIK3R2 in OGCs. Further analysis showed that PI3K/AKT/mTOR signaling pathway took part in miR-126-3p/PIK3R2 mediated proliferation and apoptosis in OGCs. In rat POF model, administration of miR-126-3p-hucMSCs-exosomes increased E2 and AMH levels, increased body and reproductive organ weights and follicle counts, and reduced FSH levels. But more importantly, immunohistochemistry results indicated miR-126-3p-hucMSCs-exosomes significantly promoted ovarian angiogenesis and inhabited apoptosis in POF rats. Additionally, the analysis of angiogenic-related factors and apoptosis-related factors showed miR-126-3p-hucMSCs-exosomes had pro-angiogenesis and anti-apoptosis effect in rat ovaries. Conclusions Our findings revealed that hucMSCs-derived exosomes carrying miR-126-3p promote angiogenesis and attenuate OGCs apoptosis in POF, which highlighted the potential of exosomes containing miR-126-3p as an effective therapeutic strategy for POF treatment.

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Stem Cell Paracrine Signaling for Treatment of Premature Ovarian Insufficiency

Cited by 18 publications

References 132 publications

Cell-Free Fat Extract Improves Ovarian Function and Fertility in Mice With Advanced Age

Cell-Free Fat Extract Improves Ovarian Function and Fertility in Mice With Advanced Age

Placental mesenchymal stem cells ameliorate NLRP3 inflammasome induced ovarian insufficiency by modulating macrophage M2 polarization

miR-126-3p containing exosomes derived from human umbilical cord mesenchymal stem cells promote angiogenesis and attenuate ovarian granulosa cell apoptosis in a preclinical rat model of premature ovarian failure

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