Exosomal miR-143-3p derived from follicular fluid promotes granulosa cell apoptosis by targeting BMPR1A in polycystic ovary syndrome

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.

The Improvement of Porcine In Vitro Embryo Development through Regulating Autophagy by miRNA-143 Inhibition

“…When we analyzed the effects on apoptosis, we observed that miR-143 inhibition resulted in a reduction of the apoptosis-related gene, Caspase3, while the miR-143 mimic increased expression of Caspase3 . This finding is supported by those from a previous study demonstrating that miR-143 triggered apoptosis by inhibiting the Smad1/5/8 pathways and regulating the expression of BMP-specific type 1 ( BMPR1A ) [ 11 ]. In addition, an examination of FSHR , a gene target of miR-143 [ 6 ], revealed that miR-143 inhibitors and mimics increased and decreased the mRNA expression of FSHR , respectively.…”

“…A recent study in patients with ovarian disease noted that miR-143 was highly expressed in the follicular fluid and further increased apoptosis by inhibiting the Smad1/5/8 pathways [ 11 ]. Research on gastrointestinal disease showed that miR-143 exerted a negative effect, triggering inflammation through the regulation of autophagy by targeting ATG2B [ 12 ].…”

Programmed cell death 4: A novel player in the pathogenesis of polycystic ovary syndrome

“…Although it is not thoroughly elucidated which mechanisms are behind the cessation of antral follicle development in PCOS, the apoptosis of GCs triggered by altered follicular niche, for example, androgen excess, was suggested as one of the most potential mechanisms in this regard 65 . Interestingly, an accumulating body of evidence obtained from animal models as well as humans demonstrated that PCOS gives rise to a remarkable increase in GC apoptosis 66–69 . From the molecular perspective, the mRNA expression of numerous p53 target genes was upregulated in GCs of women with PCOS, most of which are implicated in the activation of intrinsic and extrinsic pathways of apoptosis, including BAX, BID, FAS, caspase‐8, and PTEN.…”

Plasma exosomes and contained MiRNAs affect the reproductive phenotype in polycystic ovary syndrome

“…8 Several studies reported many differentially expressed miRNAs in exosomes of follicular fluid of PCOS women, which can promote granulosa cell apoptosis and follicular dysplasia. [9][10][11][12] PCOS, as a systemic disease, compromises many organs, not merely the ovaries. Che X et al found miR-27a-5p in serum exosomes was upregulated and affected TGF-β signaling pathways leading to increased risk of endometrial cancer in PCOS patients.…”

“…In recent years, exosomes and contained miRNAs have been found to be crucial in the pathogenesis of PCOS 8 . Several studies reported many differentially expressed miRNAs in exosomes of follicular fluid of PCOS women, which can promote granulosa cell apoptosis and follicular dysplasia 9–12 . PCOS, as a systemic disease, compromises many organs, not merely the ovaries.…”