Restoring Ovarian Function With Human Placenta-Derived Mesenchymal Stem Cells in Autoimmune-Induced Premature Ovarian Failure Mice Mediated by Treg Cells and Associated Cytokines

Abstract

Regulatory T (Treg) cells play a key role in the regulation of autoimmunity and transplantation. Human placenta-derived mesenchymal stem cell (hPMSC) transplantation has a potential to restore ovarian dysfunction associated with premature ovarian failure (POF), while the exact function of the Treg cells in the transplantation still needs to be further investigated. In this study, hPMSCs were intravenously injected into POF mice following zona pellucida glycoprotein 3 (pZP3) treatment. Ovarian function was measured by analyzing estrous cycle, folliculogenesis, and hormone secretion, also, with the detection of apoptotic granular cells (GCs) in ovarian tissues. To determine whether immune response is involved in the regulation of ovarian function change, the population of Treg cell populations and expression of associated cytokines, for example, transforming growth factor β (TGF-β) and interferon γ (IFN-γ) were measured. After hPMSCs transplantation, the injured ovarian function is significantly improved. Also, the pZP3-treatment-induced apoptotic GCs were significantly decreased as compared with the POF mice. The transplantation of hPMSCs significantly increased the population of Treg cells which was inhibited by pZP3 treatment. The decrease in TGF-β and increase in IFN-γ in serum caused by pZP3 treatment have been reversed following hPMSCs transplantation. These findings strongly suggest that the recovery of ovarian function in POF mice is mediated via the regulation of Treg cells and production of associated cytokines following hPMSCs transplantation.

Human placenta‐derived mesenchymal stem cells inhibit apoptosis of granulosa cells induced by IRE1α pathway in autoimmune POF mice

“…These indicate that hPMSCs transplantation is beneficial for the recovery of ovarian function of POF mice. Previous studies have shown that the hPMSCs transplantation could promote follicular development, and improve the ovarian reserve capacity (Yin et al, ; Zhang et al, ). These are consistent with our results.…”

“…And during pregnancy, the women have been tested negative for human immunodeficiency virus I, hepatitis B, and hepatitis C following informed consent. The hPMSCs were isolated and cultured as previously described (Yin et al, , b). The cell membrane and intracytoplasmic molecular markers of hPMSCs were examined using flow cytometry to confirm the phenotype of hPMSCs as we previously described (Yin et al, , b).…”

“…The mice in the POF group did not receive any other treatment after the modeling procedure. 1 × 10 6 hPMSCs at sixth passages were slowly injected into the mice of POF + hPMSCs transplantation group via the tail vein one week after modeling (Park et al, ; Yin et al, , b). For comparison, the same volume of phosphate‐buffered saline (PBS) was injected into POF mice as vehicle control at the same time point.…”

“…Studies have confirmed that maintaining ER Ca 2+ homeostasis of GCs is important for ovarian follicle development (Sun et al, ). In addition, previous studies have shown that transplantation of hPMSCs improved the ovarian function of POF mice and reduced the expression of caspase‐3 activation (Yin et al, ). So based on the above, in the present study, we aimed to explore the effect of hPMSCs transplantation on the GCs apoptosis in an autoimmune POF mice model, through regulation of the expression of IRE1α pathway of ER stress in ovaries.…”

Microenvironmental changes induced by placenta-derived mesenchymal stem cells restore ovarian function in ovariectomized rats via activation of the PI3K-FOXO3 pathway

“…showed that PD-MSCs have therapeutic bene ts in mice with premature ovarian failure because they regulate regulatory T-cell activity and cytokines [18,19].…”