title: Oncostatin M-Preconditioned Mesenchymal Stem Cells Alleviate Bleomycin-Induced Pulmonary Fibrosis Through Paracrine Effects of the Hepatocyte Growth Factor.
abstract: Mesenchymal stem cells (MSCs) are widely considered for treatment of pulmonary fibrosis based on the anti-inflammatory, antifibrotic, antiapoptotic, and regenerative properties of the cells. Recently, elevated levels of oncostatin M (OSM) have been reported in the bronchoalveolar lavage fluid of a pulmonary fibrosis animal model and in patients. In this work, we aimed to prolong engrafted MSC survival and to enhance the effectiveness of pulmonary fibrosis transplantation therapy by using OSM-preconditioned MSCs. OSM-preconditioned MSCs were shown to overexpress type 2 OSM receptor (gp130/OSMRβ) and exhibited high susceptibility to OSM, resulting in upregulation of the paracrine factor, hepatocyte growth factor (HGF). Moreover, OSM-preconditioned MSCs enhanced cell proliferation and migration, attenuated transforming growth factor-β1- or OSM-induced extracellular matrix production in MRC-5 fibroblasts through paracrine effects. In bleomycin-induced lung fibrotic mice, transplantation of OSM-preconditioned MSCs significantly improved pulmonary respiratory functions and downregulated expression of inflammatory factors and fibrotic factors in the lung tissues. Histopathologic examination indicated remarkable amelioration of the lung fibrosis. LacZ-tagged MSCs were detected in the lung tissues of the OSM-preconditioned MSC-treated mice 18 days after post-transplantation. Taken together, our data further demonstrated that HGF upregulation played an important role in mediating the therapeutic effects of transplanted OSM-preconditioned MSCs in alleviating lung fibrosis in the mice. Stem Cells Translational Medicine 2017;6:1006-1017.
authors.affiliation: Graduate Institute of Biomedical Sciences, Division of Biotechnology, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan, Republic of China.
authors.forename: Ying-Wei
authors.initials: YW
authors.lastname: Lan
authors.affiliation: Department of Medical Biotechnology and Laboratory Science, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan, Republic of China.
authors.forename: Si-Min
authors.initials: SM
authors.lastname: Theng
authors.affiliation: Department of Medical Biotechnology and Laboratory Science, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan, Republic of China.|Center for Molecular and Clinical Immunology, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan, Republic of China.
authors.forename: Tsung-Teng
authors.initials: TT
authors.lastname: Huang
authors.affiliation: Department of Preclinical Sciences, Faculty of Medicine and Health Sciences, and Centre for Stem Cell Research, Universiti Tunku Abdul Rahman, Selangor, Malaysia.
authors.forename: Kong-Bung
authors.initials: KB
authors.lastname: Choo
authors.affiliation: Department of Life Sciences, National Chung Hsing University, Taichung, Taiwan, Republic of China.|Agricultural Biotechnology Center, National Chung Hsing University, Taichung, Taiwan, Republic of China.|Rong-Hsing Translational Medicine Center, National Chung Hsing University, Taichung, Taiwan, Republic of China.
authors.forename: Chuan-Mu
authors.initials: CM
authors.lastname: Chen
authors.affiliation: Department of Thoracic Medicine, Chang Gung Memorial Hospital at Linkou, Tao-Yuan, Taiwan, Republic of China.|Department of Medicine, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan, Republic of China.|Department of Internal Medicine, Chang Gung Memorial Hospital at Linkou, Tao-Yuan, Taiwan, Republic of China.
authors.forename: Han-Pin
authors.initials: HP
authors.lastname: Kuo
authors.affiliation: Graduate Institute of Biomedical Sciences, Division of Biotechnology, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan, Republic of China.|Department of Medical Biotechnology and Laboratory Science, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan, Republic of China.|Department of Thoracic Medicine, Chang Gung Memorial Hospital at Linkou, Tao-Yuan, Taiwan, Republic of China.|Molecular Medicine Research Center, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan, Republic of China.
authors.forename: Kowit-Yu
authors.initials: KY
authors.lastname: Chong
mesh_terms: D000818:Animals; D001761:Bleomycin / Q000633:toxicity*; D002478:Cells, Cultured; D005260:Female; D017228:Hepatocyte Growth Factor / Q000378:metabolism*; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000187:drug effects* / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D053683:Oncostatin M / Q000494:pharmacology*; D011658:Pulmonary Fibrosis / Q000139:chemically induced* / Q000628:therapy*
chemical_list: D053683:Oncostatin M; D001761:Bleomycin; D017228:Hepatocyte Growth Factor
keywords: Bleomycin-induced pulmonary fibrosis; Hepatocyte growth factor; Oncostatin M; Preconditioning; Stem cells