Overexpression of HOXB4 Promotes Protection of Bone Marrow Mesenchymal Stem Cells Against Lipopolysaccharide-Induced Acute Lung Injury Partially Through the Activation of Wnt/β-Catenin Signaling

Lin, Shan; Chen, Qingui; Zhang, Lishan; Ge, Shanhui; Luo, Yuling; He, Wanmei; Xu, Caixia; Zeng, Mian

PURPOSE: Pulmonary vascular endothelial cell (EC) injury is recognized as one of the pathological factors of acute lung injury/acute respiratory distress syndrome (ALI/ARDS). Bone marrow mesenchymal stem cell (BMSC)-based cytotherapy has attracted substantial attention over recent years as a promising therapeutic approach for ALI/ARDS; however, its use remains limited due to inconsistent efficacy. Currently, gene modification techniques are widely applied to MSCs. In the present study, we aimed to investigate the effect of BMSCs overexpressing Homeobox B4 (HOXB4) on lipopolysaccharide (LPS)-induced EC injury. METHODS: We used LPS to induce EC injury and established EC-BMSC coculture system using transwell chambers. The effect of BMSCs on ECs was explored by detecting EC proliferation, apoptosis, migration, tube formation, and permeability, and determining whether the Wnt/β-catenin pathway is involved in the regulatory mechanism using XAV-939, inhibitor of Wnt/ β-catenin. RESULTS: As compared to BMSC(WT), BMSC(HOXB4) coculture promoted EC proliferation, migration, and tube formation after LPS stimulation and attenuated LPS-induced EC apoptosis and vascular permeability. Mechanistically, BMSC(HOXB4) coculture prevented LPS-induced EC injury by activating the Wnt/β-catenin pathway, which is partially reversible by XAV-939. When cocultured with BMSC(HOXB4), pro-inflammatory factors were dramatically decreased and anti-inflammatory factors were greatly increased in the EC medium compared to those in the LPS group (P<0.05). Additionally, when compared to BMSC(WT) coculture, the BMSC(HOXB4) coculture showed an enhanced modulation of IL-6, TNF-α, and IL-10, but there was no statistically significant effect on IL-1β and IL-4. CONCLUSION: Coculturing of BMSC(HOXB4) prevented LPS-induced EC injury by reversing the inactivation of the Wnt/β-catenin signaling pathway. An in vivo study remains warranted to ascertain whether engraftment of BMSC(HOXB4) can be an attractive strategy for the treatment of ALI/ARDS.