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.