Evidence that bone marrow-derived mesenchymal stem cells reduce epithelial permeability following phosgene-induced acute lung injury via activation of wnt3a protein-induced canonical wnt/β-catenin signaling

Jing ZhangDepartment of Intensive Care Unit, Center of Emergency & Intensive Care Unit, Jinshan Hospital, Fudan University, Shanghai, China, ;Department of Intensive Care Unit, Medical Research Center of Chemical Injury, Jinshan Hospital, Fudan University, Shanghai, China, ;Department of Intensive Care Unit, Medical Center of Radiation Injury, Jinshan Hospital, Fudan University, Shanghai, China, and

Yiru ShaoDepartment of Intensive Care Unit, Center of Emergency & Intensive Care Unit, Jinshan Hospital, Fudan University, Shanghai, China, ;Department of Intensive Care Unit, Medical Research Center of Chemical Injury, Jinshan Hospital, Fudan University, Shanghai, China, ;Department of Intensive Care Unit, Medical Center of Radiation Injury, Jinshan Hospital, Fudan University, Shanghai, China, and

Daikun HeDepartment of Intensive Care Unit, Center of Emergency & Intensive Care Unit, Jinshan Hospital, Fudan University, Shanghai, China, ;Department of Intensive Care Unit, Medical Research Center of Chemical Injury, Jinshan Hospital, Fudan University, Shanghai, China, ;Department of Intensive Care Unit, Medical Center of Radiation Injury, Jinshan Hospital, Fudan University, Shanghai, China, and

Lin ZhangDepartment of Intensive Care Unit, Center of Emergency & Intensive Care Unit, Jinshan Hospital, Fudan University, Shanghai, China, ;Department of Intensive Care Unit, Medical Research Center of Chemical Injury, Jinshan Hospital, Fudan University, Shanghai, China, ;Department of Intensive Care Unit, Medical Center of Radiation Injury, Jinshan Hospital, Fudan University, Shanghai, China, and

Guoxiong XuDepartment of Center Laboratory, Jinshan Hospital, Fudan University, Shanghai, China

Jie ShenDepartment of Intensive Care Unit, Center of Emergency & Intensive Care Unit, Jinshan Hospital, Fudan University, Shanghai, China, ;Department of Intensive Care Unit, Medical Research Center of Chemical Injury, Jinshan Hospital, Fudan University, Shanghai, China, ;Department of Intensive Care Unit, Medical Center of Radiation Injury, Jinshan Hospital, Fudan University, Shanghai, China, and Correspondence[email protected]

Abstract

An increase in epithelial cell permeability has been proposed to contribute to phosgene-induced acute lung injury (ALI). However, no specific and effective means for blocking increases in permeability are currently available. Cell-based therapy using bone marrow-derived mesenchymal stem cells (MSCs) is an attractive new approach. Canonical wnt/β-catenin signaling has been demonstrated to contribute to both epithelial cell injury and repair mechanisms in ALI. The goal of our study was to determine the effects of MSCs on epithelial permeability in phosgene-induced ALI in Sprague–Dawley (SD) rats and identify changes in major components of the wnt3a/β-catenin signaling pathway during this process. Epithelial cell permeability was evaluated by measuring total protein, albumin, keratinocyte growth factor, and occludin in bronchoalveolar lavage fluid and lung tissue. MSCs-harboring lentiviral vectors expressing green fluorescent protein (GFP) were used to determine rates of MSC engraftment at injured sites. Lung tissue was excised to evaluate changes in the levels of proteins that function in wnt3a/β-catenin signaling, including wnt3a, total β-catenin, non-phosphorylated-Ser33/37/Thr41 β-catenin, axin2, and cyclin D1 by western blot analysis. Because TGF-β1 and wnt5a can inhibit canonical wnt/β-catenin signaling, we also measured levels of TGF-β1 and wnt5a by western blotting.

Conclusions: (1) TGF-β1 and wnt5a expression correlated with inhibition of wnt3a/β-catenin signaling in our phosgene-induced ALI model and (2) exogenously supplied MSCs homed to sites of lung injury and reduced epithelial permeability likely by blocking TGF-β1- and wnt5a-mediated inhibition of wnt3/β-catenin signaling.

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Declaration of interest

The authors declare that they have no competing interests related to this study. This work was funded by National Natural Science Foundation of China (81471850), National Natural Science Foundation of China (81101412), and Jinshan District Science and Technology Commission of Shanghai (2013-3-05).

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Evidence that bone marrow-derived mesenchymal stem cells reduce epithelial permeability following phosgene-induced acute lung injury via activation of wnt3a protein-induced canonical wnt/β-catenin signaling

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Evidence that bone marrow-derived mesenchymal stem cells reduce epithelial permeability following phosgene-induced acute lung injury via activation of wnt3a protein-induced canonical wnt/β-catenin signaling

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