Work

AICAR-induced energy supply and paracrine activity of endothelial cells accelerate chronic diabetic wound healing by promoting angiogenesis and modulating macrophage reprogramming

Year: 2026

Type: article

Abstract: Chronic diabetic wound healing is severely hampered by endothelial cell (EC) dysfunction, defective angiogenesis, and a persistent inflammatory microenvironment, yet the crosstalk between EC energy metabolism and macrophage polarization in this process remains poorly understood. Here, we identified an AMPK-dependent metabolic pathway in ECs that orchestrated both angiogenic restoration and macrophage immune reprogramming for diabetic wound repair, and translated this mechanism into a functional three-dimensional (3D) scaffold (MEWs+GelMA@AI) fabricated by melt electrospinning writing technology. Acadesine (AICAR) efficiently induced a high-energy state in ECs by activating AMPK, preserving mitochondrial ultrastructure, enhancing respiratory-chain complex activity, and increasing VEGF expression and angiogenic potential. Notably, we discovered that AI-EXO, secreted by these metabolically activated ECs, delivered GAS6 to macrophages as a key paracrine factor, thereby triggering activation of the MER/AKT pathway and driving M1-to-M2 polarization. To our knowledge, this is the first report identifying exosomal GAS6 as a mediator of EC-macrophage crosstalk in diabetic wound healing. The MEWs+GelMA@AI scaffold, characterized by a porous structure and sustained AICAR release, exhibited excellent cytocompatibility and proangiogenic activity in vitro . In vivo , the scaffold significantly accelerated diabetic wound closure by promoting neovascularization, reducing inflammatory infiltration, and increasing the M2/M1 macrophage ratio, without detectable systemic toxicity in major organs. These findings establish a critical link between EC energy metabolism and immune microenvironment remodeling, providing a potentially translatable metabolic-engineering strategy for chronic diabetic wounds. This study opens new avenues for regenerative therapies targeting metabolic-immune interactions.

Source: Materials Today Bio

DOI: 10.1016/j.mtbio.2026.103743