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

Abstract

Premature ovarian insufficiency (POI) is clinically irreversible in women aged over 40 years. Although numerous studies have demonstrated satisfactory outcomes of mesenchymal stem cell therapy, the underlying therapeutic mechanism remains unclear. Exosomes were collected from the culture medium of human umbilical cord mesenchymal stem cells (hUMSCs) and assessed by electron microscopy and Western blot (WB) analysis. Then, exosomes were added to the culture medium of cyclophosphamide (CTX)‐damaged human granulosa cells (hGCs), and the mixture was injected into the ovaries of CTX‐induced POI model mice before detection of antiapoptotic and apoptotic gene expression. Next, the microRNA expression profiles of hUMSC‐derived exosomes (hUMSC‐Exos) were detected by small RNA sequencing. The ameliorative effect of exosomal microRNA‐17‐5P (miR‐17‐5P) was demonstrated by miR‐17‐5P knockdown before assessment of ovarian phenotype and function, reactive oxygen species (ROS) levels and SIRT7 expression. Finally, SIRT7 was inhibited or overexpressed by RNA interference or retrovirus transduction, and the protein expression of PARP1, γH2AX, and XRCC6 was analyzed. The ameliorative effect of hUMSC‐Exos on POI was validated. Our results illustrated that hUMSC‐Exos restored ovarian phenotype and function in a POI mouse model, promoted proliferation of CTX‐damaged hGCs and ovarian cells, and alleviated ROS accumulation by delivering exosomal miR‐17‐5P and inhibiting SIRT7 expression. Moreover, our findings elucidated that miR‐17‐5P repressed PARP1, γH2AX, and XRCC6 by inhibiting SIRT7. Our findings suggest a critical role for exosomal miR‐17‐5P and its downstream target mRNA SIRT7 in hUMSC transplantation therapy. This study indicates the promise of exosome‐based therapy for POI treatment.

Human amnion-derived mesenchymal stem cells improved the reproductive function of age-related diminished ovarian reserve in mice through Ampk/FoxO3a signaling pathway

“…6 a) while it repressed apoptosis in granulosa, theca, and stromal cells (Fig. 5 ), demonstrating that hAMSCs might also promote oocyte maturation by improving ovarian microenvironment, consistent with previous reports [ 24 , 25 , 29 , 30 ]. Besides, serum hormone levels of AR-DOR mice were somehow rebalanced (Fig.…”

“…Furthermore, it is reported that transplantation of UCMSC functions on POI patient [ 23 ]. Further explorations demonstrate that MSCs improved ovarian function through oxidation resistance in which PI3K-FoxO3a or SIRT signal pathway is involved [ 24 , 25 ].…”

Human Amnion-Derived Mesenchymal Stem Cells Improved the Reproductive Function of Age-Related Diminished Ovarian Reserve in Mice Through Ampk/Foxo3a Signaling Pathway

“…6a) meanwhile repressed apoptosis in granulosa and stromal cells (Fig. 5), demonstrating that hAMSCs might also promote oocyte maturation by improving ovarian microenvironment, consistent with previous reports [24,25,29,30]. Besides, serum hormone levels of AR-DOR mice were rebalanced (Fig.…”

“…3c, d), meaning that they functioned by secreting cytokines [63] (Fig. 1b) and/or vesicles [24,29] rather than differentiation into tissue-speci c cells. That precise hAMSCs-secreting components effective in ovarian function repairability and the function mechanism would be explored in future research.…”

“…Furthermore, it is reported that UCMSCs is function on POI patient [23]. Further explorations demonstrate that MSCs improved ovarian function through oxidation resistance in which PI3K-FoxO3a or SIRT signal pathway is involved [24,25].…”