Lats2-Underexpressing Bone Marrow-Derived Mesenchymal Stem Cells Ameliorate LPS-Induced Acute Lung Injury in Mice

Abstract

The pathophysiology of the acute lung injury (ALI) is characterized by the damage of alveolar epithelial cells, which can be repaired by exogenous bone marrow-derived mesenchymal stem cells (BMSCs). However, the migration and differentiation abilities of BMSCs are not sufficient for the purpose, and a new approach that could strengthen the repair effects of BMSCs in ALI still needs to be clarified. We have previously proved that in vitro large tumor suppressor kinase 2- (Lats2-) underexpressing BMSCs may enhance their tissue repair effects in ALI; thus, in the present study, we tried to explore whether Lats2-underexpressing BMSCs could rescue lipopolysaccharide- (LPS-) induced ALI in vivo. BMSCs from C57BL/6 mice transfected with Lats2-interfering lentivirus vector or lentivirus blank controls were transplanted intratracheally into LPS-induced ALI mice. The retention and differentiation of BMSCs in the lung were evaluated by in vivo imaging, immunofluorescence staining, and Western blotting. The lung edema and permeability were assessed by lung wet weight/body weight ratio (LWW/BW) and measurements of proteins in bronchoalveolar lavage fluid (BALF) using ELISA. Acute lung inflammation was measured by the cytokines in the lung homogenate and BALF using RT-qPCR and ELISA, respectively. Lung injury was evaluated by HE staining and lung injury scoring. Pulmonary fibrosis was evaluated by Picrosirius red staining, immunohistochemistry for α-SMA and TGF-β1, and hydroxyproline assay and RT-qPCR for Col1α1 and Col3α1. Lats2-mediated inhibition of the Hippo pathway increased the retention of BMSCs and their differentiation toward type II alveolar epithelial cells in the lung. Furthermore, Lats2-underexpressing BMSCs improved lung edema, permeability of the lung epithelium, and lung inflammation. Finally, Lats2-underexpressing BMSCs alleviated lung injury and early pulmonary fibrosis. Our studies suggest that underexpression of Lats2 could further enhance the repair effects of BMSCs against epithelial impair and the therapeutic potential of BMSCs in ALI mice.

Improved Differentiation Ability and Therapeutic Effect of miR-23a-3p Expressing Bone Marrow-Derived Mesenchymal Stem Cells in Mice Model with Acute Lung Injury

“…In addition, miR-23a-3p downregulation was previously found to be associated with LPS-induced rat testis (12), while miR-23a-3p upregulation was detected in acute laminitis horses (27). Our study demonstrated that LPS-induced ALI markedly downregulated miR-23a-3p expression, and similar to Dong's findings (28), it also increased LWW/BW, promoted inflammatory infiltration and enhanced inflammatory factor release in vivo.…”

Hippo signaling pathway and respiratory diseases

“…Severe ALI leads to life-threatening respiratory failure with high morbidity and mortality [ 54 , 55 ]. Infiltration of inflammatory cells, increased blood-air barrier permeability, pulmonary edema, and diffuse alveolar damage are often found in ALI [ 54 , 56 , 57 ]. Meanwhile, excessive lung inflammation and apoptosis of alveolar epithelial cells (AECs) are key factors in the pathogenesis of ALI [ 52 , 56 ].…”

“…Moreover, alveolar epithelial cells are repaired by exogenous bone marrow-derived mesenchymal stem cells (BMSCs) and down-expression of LATS2 improves BMSCs repairing the tissue in ALI, thereby alleviates the pathological damage of lung tissue [ 57 ]. In addition, inhibition of hippo signaling pathway increases BMSCs retention and migration to the site of injured lung tissue and promoted the differentiation of BMSCs into AECIIs [ 57 ].…”

BMSC‐Derived Exosomes Ameliorate LPS‐Induced Acute Lung Injury by miR‐384‐5p‐Controlled Alveolar Macrophage Autophagy

“…Numerous studies provide evidence to demonstrate a therapeutic effect of bone marrow mesenchymal stem cells (BMSCs) in various clinical disorders, including ALI, in which BMSCs prevent tissue injury through different mechanisms [8,9]. Recently, several researches have indicated that the BMSCs secrete specialized membranous nanosized vesicle termed exosomes to prevent lung tissue injury [10][11][12].…”