Abstract
Polycystic ovary syndrome (PCOS) is an endocrine disorder that occurs in women of reproductive age. Anovulation caused by abnormal follicular development is still the main characteristic of PCOS patients with infertile. Granulosa cell (GC) is an important part of the follicular microenvironment, the dysfunction of which can affect follicular development. Increasing evidence indicates that exosomal miRNAs derived from the follicular fluid (FF) of patients play critical roles during PCOS. However, which follicular fluid-derived exosomal miRNAs play a pivotal role in controlling granulosa cell function and consequently follicular development remain largely unknown, as does the underlying mechanism. Herein, we showed that miR-143-3p is highly expressed in the follicular fluid exosomes of patients with PCOS and can be delivered into granulosa cells. Furthermore, functional experiments showed that translocated miR-143-3p promoted granulosa cell apoptosis, which is important in follicle development. Mechanistically, BMPR1A was identified as a direct target of miR-143-3p. Overexpression of BMPR1A reversed the effects of exosomal miR-143-3p on GC apoptosis and proliferation by activating the Smad1/5/8 signaling pathway. These results demonstrate that miR-143-3p-containing exosomes derived from PCOS follicular fluid promoted granulosa cell apoptosis by targeting BMPR1A and blocking the Smad1/5/8 signaling pathway. Our findings provide a novel mechanism underlying the roles of exosomal-miRNAs in the follicular fluid of PCOS patients and facilitate the development of therapeutic strategies for PCOS.
Highlights
Polycystic ovary syndrome (PCOS) is an endocrine disorder that occurs in women of reproductive age
We mainly focused on exosomal-miR-143-3p and explored the effect of PCOS-follicular fluid (FF) derived exosomal-miR-143-3p on the apoptosis and proliferation of ovarian Granulosa cell (GC) and analysed the underlying molecular mechanisms involved in follicular dysplasia in PCOS
We found that the pro-apoptotic gene Bax mRNA levels were significantly increased, and the anti-apoptotic gene Bcl-2 mRNA levels were significantly decreased in primary GCs in the PCOS group compared with the healthy control group (Supplementary Fig. S1)
Summary
Polycystic ovary syndrome (PCOS) is an endocrine disorder that occurs in women of reproductive age. Increasing evidence indicates that exosomal miRNAs derived from the follicular fluid (FF) of patients play critical roles during PCOS. Which follicular fluid-derived exosomal miRNAs play a pivotal role in controlling granulosa cell function and follicular development remain largely unknown, as does the underlying mechanism. Functional experiments showed that translocated miR-143-3p promoted granulosa cell apoptosis, which is important in follicle development. Abbreviations PCOS Polycystic ovary syndrome FF Follicular fluid GCs Granulosa cells Exos Exosomes TEM Transmission electron microscope IVF In vitro fertilization FSH Follicle-stimulating hormone E2 Estradiol LH Luteinizing hormone PRL Prolactin T Testosterone MII Metaphase II oocytes. Previous studies have reported that GC apoptosis affects follicle development, oocyte growth and maturation and triggers follicular atresia during the early phase of follicular development[7]. The underlying mechanism of abnormal apoptosis of GCs involved in the process of abnormal follicular development in PCOS remains unclear
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