Engineering Extracellular Vesicles Derived from 3D Cultivation of BMSCs Enriched with HGF Ameliorate Sepsis‐Induced Lung Epithelial Barrier Damage
Yong Chen, Feihong Lin, Tong Zhang, Zhuoran Xiao, Yuanli Chen, Dongsheng Hua, Yu Wang, Juan Wei, Jin Tian, Xin Lv
Abstract
Sepsis is a critical condition with high mortality, often leading to acute lung injury (ALI) due to uncontrolled inflammatory responses and alveolar epithelial damage. Extracellular vesicles (EVs), particularly mesenchymal stem cell-derived EVs, have shown therapeutic potential in sepsis-related organ dysfunction by transferring RNAs and proteins. However, their clinical use is limited by low efficacy and yield. To address this, 3D-cultured MSCs (3D-MSCs) are generated using MicroTissues 3D Petri Dish. These 3D-MSCs demonstrate improved protection and proliferation of MLE-12 cells in vitro. Mechanistic studies are conducted to explore the enhanced protective effects of 3D-MSCs derived EVs (3D-EVs) in a septic-ALI model. Proteomic and molecular analyses of 3D-EVs revealed that they are enriched in hepatocyte growth factor (HGF). HGF helps maintain the barrier function of damaged alveolar epithelium through the PI3K-AKT signaling pathway. Overall, 3D-EVs effectively ameliorate sepsis-induced ALI and enhance prognosis by enriching and delivering HGF, suggesting that their application represents a promising treatment strategy for septic ALI.