Human Adipose-Derived Mesenchymal Stem Cells Ameliorate Elastase-Induced Emphysema in Mice by Mesenchymal–Epithelial Transition

Abstract

Nobuhiro Fujioka,1 Masahiro Kitabatake,2 Noriko Ouji-Sageshima,2 Takahiro Ibaraki,1 Makiko Kumamoto,1 Yukio Fujita,1 Shigeto Hontsu,1 Motoo Yamauchi,1 Masanori Yoshikawa,1 Shigeo Muro,1 Toshihiro Ito2 1Department of Respiratory Medicine, Nara Medical University, Kashihara, Nara, Japan; 2Department of Immunology, Nara Medical University, Kashihara, Nara, JapanCorrespondence: Toshihiro ItoDepartment of Immunology, Nara Medical University, 840 Shijo-cho, Kashihara, Nara, 634-8521, JapanTel [phone]Fax [phone]Email [email protected]: Chronic obstructive pulmonary disease (COPD) is a worldwide problem because of its high prevalence and mortality. However, there is no fundamental treatment to ameliorate their pathological change in COPD lung. Recently, adipose-derived mesenchymal stem cells (ADSCs) have attracted attention in the field of regenerative medicine to repair damaged organs. Moreover, their utility in treating respiratory diseases has been reported in some animal models. However, the detailed mechanism by which ADSCs improve chronic respiratory diseases, including COPD, remains to be elucidated. We examined whether human ADSCs (hADSCs) ameliorated elastase-induced emphysema and whether hADSCs differentiated into alveolar epithelial cells in a murine model of COPD.Methods: Female SCID-beige mice (6 weeks old) were divided into the following four groups according to whether they received an intratracheal injection of phosphate-buffered saline or porcine pancreatic elastase, and whether they received an intravenous injection of saline or hADSCs 3 days after intratracheal injection; Control group, hADSC group, Elastase group, and Elastase-hADSC group. We evaluated the lung function, assessed histological changes, and compared gene expression between hADSCs isolated from the lung of Elastase-hADSC group and naïve hADSCs 28 days after saline or elastase administration.Results: hADSCs improved the pathogenesis of COPD, including the mean linear intercept and forced expiratory volume, in an elastase-induced emphysema model in mice. Furthermore, hADSCs were observed in the lungs of elastase-treated mice at 25 days after administration. These cells expressed genes related to mesenchymal–epithelial transition and surface markers of alveolar epithelial cells, such as TTF-1, β-catenin, and E-cadherin.Conclusion: hADSCs have the potential to improve the pathogenesis of COPD by differentiating into alveolar epithelial cells by mesenchymal–epithelial transition.Keywords: chronic obstructive pulmonary disease, mesenchymal–epithelial transition, adipose derived mesenchymal stem cell, pulmonary function test

Keywords

• chronic obstructive pulmonary disease
• mesenchymal-epithelial transition
• adipose derived mesenchymal stem cell
• pulmonary function test