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

Abstract

Shan Lin,1,2 Qingui Chen,1,2 Lishan Zhang,1,2 Shanhui Ge,1,2 Yuling Luo,1,2 Wanmei He,1,2 Caixia Xu,3 Mian Zeng1,2 1Department of Medical Intensive Care Unit, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510080, People’s Republic of China; 2Institute of Pulmonary Diseases, Sun Yat-sen University, Guangzhou, Guangdong, People’s Republic of China; 3Research Center of Translational Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, People’s Republic of ChinaCorrespondence: Mian ZengDepartment of Medical Intensive Care Unit, The First Affiliated Hospital, Sun Yat-sen University, No. 58 Zhongshan Road 2, Guangzhou, Guangdong, 510080, People’s Republic of ChinaEmail [email protected] XuResearch Center of Translational Medicine, The First Affiliated Hospital, Sun Yat-sen University, No. 58 Zhongshan Road 2, Guangzhou, Guangdong, 510080, People’s Republic of ChinaEmail [email protected]: 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 BMSCWT, BMSCHOXB4 coculture promoted EC proliferation, migration, and tube formation after LPS stimulation and attenuated LPS-induced EC apoptosis and vascular permeability. Mechanistically, BMSCHOXB4 coculture prevented LPS-induced EC injury by activating the Wnt/β-catenin pathway, which is partially reversible by XAV-939. When cocultured with BMSCHOXB4, 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 BMSCWT coculture, the BMSCHOXB4 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 BMSCHOXB4 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 BMSCHOXB4 can be an attractive strategy for the treatment of ALI/ARDS.Keywords: acute lung injury, mesenchymal stem cells, endothelial cells, HOXB4

Keywords

• acute lung injury
• mesenchymal stem cells
• endothelial cells
• hoxb4