Therapeutic Effects of Wnt5a-Overexpressing Bone Marrow Mesenchymal Stem Cells on Endothelial Barrier Repair in Acute Lung Injury.

BACKGROUND: Acute lung injury/acute respiratory distress syndrome (ALI/ARDS), a common complication of sepsis, is critically characterized by disruption of the alveolar-capillary barrier. The use of mesenchymal stem cells (MSCs) has emerged as a promising therapeutic strategy for ARDS owing to their potent paracrine effects. Wingless-type MMTV integration site family member 5A(Wnt5a) is a secreted protein with context-dependent effects on angiogenesis. This study aimed to investigate whether Wnt5a contributes to bone marrow-derived MSC (BMSC)-mediated repair of endothelial injury and whether Wnt5a-overexpressing BMSCs improve outcomes in an ALI animal model. METHODS: Lipopolysaccharide (LPS) was used to induce endothelial cell (ECs) injury in vitro. EC proliferation, migration, tube formation and permeability, together with the expression of the junctional proteins zonula occludens-1 (ZO-1) and vascular endothelial cadherin (VE-cadherin) and the apoptosis-related proteins Bax and Bcl-2, were assessed after coculture with genetically modified BMSCs. In vivo, ALI was induced in mice by intraperitoneal administration of LPS. Lung histopathology, the lung wet-to-dry weight ratio, cytokine concentrations in bronchoalveolar lavage fluid (BALF) and serum, Evans blue extravasation, and the expression of junctional and apoptosis-related proteins were evaluated. PI3K/AKT signaling was examined as a potential pathway associated with the observed effects. RESULTS: Compared with the vector-BMSCs, Wnt5a-overexpressing BMSCs increased the proliferation, migration, and tube formation of LPS-injured ECs; reduced endothelial permeability; preserved junctional protein expression; and shifted apoptosis-related protein expression towards an anti-apoptotic profile. Wnt5a knockdown attenuated these responses. In vivo, treatment with Wnt5a-overexpressing BMSCs was associated with less histological lung injury, lower inflammatory cytokine concentrations and a similar shift in apoptosis-related protein expression after LPS challenge. These protective effects were accompanied by enhanced PI3K/AKT signaling. CONCLUSIONS: Wnt5a overexpression optimized the protective effects of BMSCs against ALI in vivo and protected against LPS-induced EC barrier dysfunction in vitro, accompanied by enhanced PI3K/AKT signaling.