Abstract

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.