Metabolic Reprogramming by Lactate Unlocks a Pro-Survival Code in MSCs: The miR-195-3p/Oct4/VEGF Axis in Heart Repair

Mesenchymal stem cell (MSC) therapy shows limited efficacy for myocardial infarction, primarily due to poor cell survival under ischemic stress. While hypoxia-regulated miRNAs are implicated in MSC function, the specific role of miR-195-3p and its potential modulation through metabolic preconditioning remain unexplored. Here, we performed miRNA sequencing of hypoxic MSCs to identify key regulators. The miR-195-3p/Oct4 interaction was validated via luciferase reporter assays, qPCR, and western blotting. MSC survival, apoptosis, and angiogenic capacity were assessed under hypoxia. Rat myocardial infarction models received MSCs with modified miR-195-3p/Oct4 expression or lactate preconditioning, followed by comprehensive evaluation of cardiac function, histopathology, and metabolic remodeling. Hypoxia markedly upregulated miR-195-3p while suppressing Oct4 in MSCs. Mechanistically, miR-195-3p directly targeted Oct4, impairing MSC survival under hypoxic stress. Lactate preconditioning restored Oct4 expression and enhanced MSC resilience. In infarcted hearts, lactate-preconditioned or Oct4-overexpressing MSCs significantly improved cardiac function, reduced fibrosis, and promoted angiogenesis compared to controls—benefits abolished by Oct4 knockdown. Oct4 restoration augmented glycolytic metabolism through GLUT1/HK2 upregulation and amplified VEGF/VEGFR2/Akt signaling. Conversely, miR-195-3p overexpression suppressed glycolysis and angiogenesis, effects rescued by Oct4 co-expression. Lactate preconditioning enhances MSC therapeutic efficacy by disrupting miR-195-3p-mediated Oct4 suppression, thereby promoting metabolic adaptation and VEGF-driven angiogenesis in ischemic myocardium. Targeting the miR-195-3p/Oct4/VEGF axis represents a promising strategy to optimize MSC-based cardiac regeneration.