Bone Marrow Mesenchymal Stromal Cells and Their Derived Extracellular Vesicles Protect Pancreatic Beta‐TC‐6 Cells From Hypoxia‐Induced Injury via miR‐539‐3p‐Mediated Downregulation of CD36 Expression

Bone marrow mesenchymal stromal cells (BMSCs) have been shown to enhance the function of pancreatic beta-cells under hypoxic conditions. However, the precise mechanisms underlying this protective effect remain elusive. In this study, we established a hypoxic beta-cell model using murine pancreatic beta-TC-6 cells to investigate the protective effect and mechanism of BMSCs and their secreted extracellular vesicles (BMSC-EVs) on hypoxic β cells. Our findings reveal that coculture with BMSCs or BMSC-EVs significantly enhances the viability and survival of hypoxic beta-TC-6 cells. Molecularly, hypoxic conditions trigger an upregulation of CD36 in beta-TC-6 cells, a response that is counteracted by BMSCs or BMSC-EVs. Through a screening process for microRNAs (miRNAs) capable of degrading CD36 mRNA, we identified miR-539-3p as a potent suppressor of CD36 expression. The miR-539-3p mimic was found to bolster the viability of hypoxic beta-TC-6 cells, concurrently reducing CD36 mRNA levels by targeting its 3' untranslated region (3'UTR). In contrast, the miR-539-3p inhibitor abrogates the protective effects of BMSCs and BMSC-EVs on these cells. Additionally, knockdown of CD36 in hypoxic beta-TC-6 cells restores the protective function mitigated by miR-539-3p inhibition. In aggregate, these results suggest that BMSCs and BMSC-EVs shield beta-TC-6 cells from hypoxia-induced injury through miR-539-3p-mediated downregulation of CD36, underscoring the therapeutic potential of targeting the miR-539-3p-CD36 axis to enhance pancreatic beta-cell function in diabetic patients.