Mesenchymal stem cells receive adaptive islet-derived <i>miR-151</i>-containing sEVs to promote β cell compensation in obesity.

Abstract

Pancreatic islets respond to obesity-related insulin resistance by increasing β cell mass and insulin secretion. However, the molecular mechanisms behind this vital compensation are not fully understood. This study shows that adaptive islet-derived small extracellular vesicles (aid-sEVs) play a key role in β cell adaptation in obesity. Aid-sEV production rises under hyperlipidemic conditions, and uptake by adjacent cells occurs via F11R-mediated recognition. Mesenchymal stem cells (MSCs) act as downstream effectors after they internalize aid-sEVs, promoting β cell-adaptive responses. These vesicles deliver <i>miR-151</i> to MSCs, triggering <i>miR-151-</i>dependent cellular reprogramming toward a Wnt-secreting phenotype. Restoration of <i>miR-151</i> in microRNA-deficient aid-sEVs restores their proadaptive effects on β cells. <i>Klf9</i>, a direct target of <i>miR-151</i>, is involved in regulating MSC proliferation and WNT secretion by controlling <i>Wnt3a</i> and <i>Ccnd1</i> transcription. These findings reveal a critical pathway controlling β cell compensation in diet-induced obesity and indicate that targeted enhancement of aid-sEV secretion could be a therapeutic strategy to counteract β cell dysfunction in diabetic patients.