Induced Pluripotent Stem Cells Attenuate Endothelial Leakage in Acute Lung Injury via Tissue Inhibitor of Metalloproteinases-1 to Reduce Focal Adhesion Kinase Activity.

Abstract

Induced pluripotent stem cells (iPSCs) can reduce the severity of endotoxin-induced acute lung injury (ALI). However, the interaction between iPSCs and vascular endothelium remains unclear. In this study, we investigated the effects of iPSCs in moderating pulmonary endothelial leakage in endotoxin-induced ALI. Murine iPSCs were delivered intravenously to male C57BL/6 mice (8-12 weeks old) 4 hours after intratracheal lipopolysaccharide (LPS) delivery. Histology, blood and bronchoalveolar lavage fluid (BALF) cytokine and junctional protein assays, and regulatory signaling pathway assays were performed 24 hours later. Human umbilical vein endothelial cells (HUVECs) were used as a model of junctional protein-expressing cells and stimulated with LPS. Our results showed that iPSC treatment alleviated histological signs of ALI, protein leakage, and proinflammatory cytokines. iPSC therapy restored vascular endothelial cadherin (VE-cadherin) expression in ALI mouse lungs. In HUVECs, human iPSCs (hiPSCs) restored disrupted VE-cadherin expression and reduced the activity of Snail and focal adhesion kinase (FAK) phosphorylation in Tyr397 in response to LPS. iPSC-conditioned medium contained extra antiangiogenic factor of tissue inhibitor of metalloproteinases-1 (TIMP-1) compared with control medium. TIMP-1 inhibition diminished the beneficial effects of iPSC-conditioned medium in ALI mice. Our study suggested that iPSCs attenuate endothelial cell leakage in endotoxin-induced ALI via a mechanism involving TIMP-1 and the FAK/Snail pathway. Stem Cells 2019;37:1516-1527.