Mesenchymal stem cells‐derived exosomal microRNA‐21‐5p downregulates PDCD4 and ameliorates erectile dysfunction in a rat model of diabetes mellitus

Abstract

Erectile dysfunction (ED) is a common comorbidity in males with diabetes mellitus (DM), whose pathogenesis might be induced by dysregulation of corpus cavernosum smooth muscle cells (CCSMCs). Gene Expression Omnibus repository‐based analysis identified the differentially expressed PDCD4 in DM rats. PDCD4 has also been determined as a putative gene under the regulatory control of microRNA‐21‐5p (miR‐21‐5p). This study aimed to further determine the functional role of miR‐21‐5p in CCSMCs in a rat model of diabetes mellitus‐induced erectile dysfunction (DMED). CCSMCs were isolated from penile cavernous tissue and cultured in high glucose (HG) medium. The expression of miR‐21‐5p and/or PDCD4 was altered in CCSMCs, as directly or indirectly measured by CCK‐8 assay, flow cytometry, and TUNEL assays. Furthermore, exosomes were isolated from mesenchymal stem cells (MSCs) transfected with miR‐21‐5p mimic or miR‐21‐5p inhibitor and co‐cultured with CCSMCs. DMED rats were injected with lentivirus carrying PDCD4/siRNA‐PDCD4 plasmids, or exosomes from MSCs containing miR‐21‐5p‐agomir to explore their roles in vivo. The experimental data validated that PDCD4 was upregulated in cavernous tissue of DMED rats. miR‐21‐5p targeted and inhibited PDCD4. miR‐21‐5p was enriched in MSC‐exosomes. Moreover, PDCD4 downregulation, miR‐21‐5p elevation or MSC‐derived exosomal miR‐21‐5p reduced apoptosis and enhanced proliferation of CCSMCs cultured in HG medium. PDCD4 silencing or miR‐21‐5p‐containing MSC‐exosomes improved erectile function and smooth muscle density in DMED rats. Collectively, our findings suggested that MSC‐derived exosomal miR‐21‐5p suppressed PDCD4 expression and ED in rats with DM.

Noncoding RNAs from tissue-derived small extracellular vesicles: Roles in diabetes and diabetic complications

“…BM-MSC-derived sEV miR-146a was also proven to protect against high glucose-induced β-cell dysfunction by reversing β-cell dedifferentiation [ 72 ]. In addition, BM-MSC-derived sEV miR-21 attenuated erectile dysfunction in diabetic rats [ 75 ], suggesting that the miRNA cargoes in MSCs highly contribute to their protective effects against diabetes and diabetic complications. Moreover, lncRNAs carried by BM-MSC-derived sEVs have a beneficial effect on diabetic complications.…”

Mesenchymal Stem Cell Exosomes as a New Strategy for the Treatment of Diabetes Complications

“…MSC-Exos contain pro-angiogenic miRNAs (miR-126, miR-130a, and miR-132) and anti-fibrotic miRNAs (miR-let7b and miR-let7c), which may increase the proliferation of vascular endothelial cells and smooth muscle cells in the cavernous body by increasing the proliferation of vascular endothelial cells and the expression of smooth muscle markers (α-SMA) and anti-apoptotic proteins (Bcl-2) to alleviate ED ( 67 , 68 ). In addition, MSC-Exos reduced apoptosis and promoted the proliferation of cavernous smooth muscle cells by delivering miR-21-5p to target programmed cell death 4, and significantly improved erectile function and smooth muscle density in DM rats ( 70 ).…”

The Role of Mesenchymal Stromal Cells-Derived Small Extracellular Vesicles in Diabetes and Its Chronic Complications

“…Huo et al. ( 22 ) explained that miR-21-5p delivered by MSC-sEVs can inhibit the expression of PDCD4 in T1DM rats, thereby stimulating the proliferation of corpus caverno-sum smooth muscle cells (CCSMCs), inhibiting CCSMCs apoptosis, and improving DED. These findings may provide new insights into the role of MSC-sEVs in the innovative treatment of DED.…”