AICAR-induced energy supply and paracrine activity of endothelial cells accelerate chronic diabetic wound healing by promoting angiogenesis and modulating macrophage reprogramming.
- 1Department of Orthopedic Surgery, The Lingnan Hospital of Sun Yat-Sen University, Guangzhou, 510630, China.
- 2Department of General Surgery, The Second Clinical Medical College, Lanzhou University, Lanzhou, 730030, China.
- 3Department of Urology, Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510655, China.
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.
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BibTeX
@article{su2026aicarinduced,
title = {{AICAR-induced energy supply and paracrine activity of endothelial cells accelerate chronic diabetic wound healing by promoting angiogenesis and modulating macrophage reprogramming.}},
author = {Hengxian Su and Chang Liu and Yusheng Cheng and Wenping Cheng and Anqi Xu and Daoyuan Hu and Hongyu Shi and Mengshi Huang and Hao Yuan and Chi Huang and Yaxian Huang and Shixing Su and Chuanzhi Duan and Xin Feng},
journal = {Materials today. Bio},
year = {2026},
month = oct,
doi = {10.1016/j.mtbio.2026.103743},
url = {https://europepmc.org/article/MED/42899161},
note = {CC BY},
}
RIS
TY - JOUR
TI - AICAR-induced energy supply and paracrine activity of endothelial cells accelerate chronic diabetic wound healing by promoting angiogenesis and modulating macrophage reprogramming.
AU - Hengxian Su
AU - Chang Liu
AU - Yusheng Cheng
AU - Wenping Cheng
AU - Anqi Xu
AU - Daoyuan Hu
AU - Hongyu Shi
AU - Mengshi Huang
AU - Hao Yuan
AU - Chi Huang
AU - Yaxian Huang
AU - Shixing Su
AU - Chuanzhi Duan
AU - Xin Feng
PY - 2026
DA - 2026/10/09
JO - Materials today. Bio
DO - 10.1016/j.mtbio.2026.103743
UR - https://europepmc.org/article/MED/42899161
AB - 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.
SN - 2590-0064
ER -