Mesenchymal stem cells with downregulated Hippo signaling attenuate lung injury in mice with lipopolysaccharide-induced acute respiratory distress syndrome

Mesenchymal stem cell (MSC)-mediated repair of injured alveolar epithelial cells is a promising potential cure for acute respiratory distress syndrome (ARDS); however, the repairing effect of MSCs is limited by poor homing and differentiation. Our previous study revealed that the inhibition of the Hippo signaling pathway promotes the proliferation, migration and differentiation of MSCs in vitro, leading to the hypothesis that MSCs with downregulated Hippo signaling could further ameliorate lipopolysaccharide (LPS)-induced ARDS in vivo. In the current study, mouse bone marrow-derived MSCs (mMSCs) with downregulated Hippo signaling were constructed by shRNA-mediated knockdown of large tumor suppressor kinase 1 (Lats1) and were intratracheally administered to LPS-induced mouse models of ARDS. The inhibition of Hippo signaling increased the retention of mMSC in ARDS lung tissue and their differentiation toward alveolar type II epithelial cells. Furthermore, mMSCs with downregulated Hippo signaling led to a decreased lung wet weight/body weight ratio, decreased total protein and albumin concentrations in bronchoalveolar lavage fluid, decreased levels of proinflammatory factors and increased levels of anti-inflammatory factors. Finally, mMSCs with downregulated Hippo signaling improved pathological changes and decreased pulmonary fibrosis in lungs of mice with ARDS. These results suggest that the inhibition of the Hippo signaling pathway in mouse mMSCs by knockdown of Lats1 could further improve the protective effects of mMSCs against epithelial damage and the therapeutic potential of mMSCs on mice with ARDS.