TLR2-PI3K/Akt mediated microbe-mimetic priming boosts the therapeutic paracrine function of GelMA-Encapsulated MSCs for diabetic wound regeneration

作者：Feng Tian, Yue Kong, Qinghua Liu, Shuoji Zhu, Xu Guo, Yuanshuai Su, Bingyang Yu, Chao Zhang, Dongzhen Zhu, Li Zhao, Wei Song, Yi Kong, Xiangye Yin, Yuyan Huang, Yaxin Tan, Mengde Zhang, Jinpeng Du, Liting Liang, Jianjun Li, Ping Zhu, Xiaobing Fu, Sha Huang · 发表于：Bioactive Materials · 年份：2025 · DOI：10.1016/j.bioactmat.2025.10.007 · 被引用次数：4 · 研究领域：Wound Healing and Treatments、Mesenchymal stem cell research、Tissue Engineering and Regenerative Medicine

Chronic diabetic wounds remain a major clinical challenge due to impaired angiogenesis and dysregulated immune homeostasis. While mesenchymal stem cell (MSC) therapy holds promise, poor survival and inconsistent paracrine function limit efficacy. Herein, we present a novel biohybrid strategy that synergistically combines microbe-mimetic preconditioning of MSCs with bacterial cell wall components (peptidoglycan, PGN and lipoteichoic acid, LTA) and their sustained delivery within a gelatin methacryloyl (GelMA) hydrogel (plMSC-GelMA) to overcome these limitations. We demonstrate that dual PGN/LTA priming uniquely activates MSCs via Toll-like receptor 2 (TLR2), triggering the PI3K/Akt pathway and profoundly enhancing their pro-angiogenic (e.g., VEGF) and immunomodulatory (e.g., IL-10, TGF-β) secretome, promoting endothelial cell function and M2 macrophage polarization in vitro. Encapsulation within biocompatible GelMA hydrogel ensured prolonged viability and localized release of these potent factors. In both acute and diabetic murine wound models, plMSC-GelMA significantly accelerated wound closure, surpassing unprimed MSC-GelMA or GelMA alone. This was driven by enhanced neovascularization (CD31+/α-SMA+) and a shift towards pro-healing M2 macrophages. Mechanistic studies confirmed the pivotal role of the TLR2-PI3K/Akt axis, as genetic (siRNA) or pharmacological (LY294002) inhibition abolished the enhanced therapeutic benefits of plMSCs. This study uncovers a microbiota-inspired ...