title: Hepatocyte Growth Factor Is Required for Mesenchymal Stromal Cell Protection Against Bleomycin-Induced Pulmonary Fibrosis.
abstract: : The incidence of idiopathic pulmonary fibrosis is on the rise and existing treatments have failed to halt or reverse disease progression. Mesenchymal stromal cells (MSCs) have potent cytoprotective effects, can promote tissue repair, and have demonstrated efficacy in a range of fibrotic lung diseases; however, the exact mechanisms of action remain to be elucidated. Chemical antagonists and short hairpin RNA knockdown were used to identify the mechanisms of action used by MSCs in promoting wound healing, proliferation, and inhibiting apoptosis. Using the bleomycin induced fibrosis model, the protective effects of early or late MSC administration were examined. The role for hepatocyte growth factor (HGF) in MSC protection against bleomycin lung injury was examined using HGF knockdown MSC. Terminal deoxynucleotidyl transferase (TdT) dUTP nick-end labeling assay was performed on ex vivo lung sections to examine the effects of MSC on apoptosis. MSC conditioned media (CM) enhanced wound closure and inhibited apoptosis of pulmonary cells in vitro. HGF was required for MSC CM enhancement of epithelial cell proliferation and inhibition of apoptosis. In contrast, MSC required COX-2 for CM to inhibit fibroblast proliferation. In a murine model, early administration of MSC protected against bleomycin induced lung fibrosis and correlated with reduced levels of the proinflammatory cytokine interleukin-1β, reduced levels of apoptosis, and significantly increased levels of HGF. These protective effects were in part mediated by MSC derived HGF as HGF knockdown MSC were unable to protect against fibrosis in vivo. These findings delineate the mechanisms of MSC protection in a preclinical model of fibrotic lung disease.
  
  
  
  The mechanisms used by mesenchymal stromal cells (MSCs) in mediating protective effects in chronic models of lung disease are not understood and remain to be elucidated. These findings from in vitro studies highlight an important role for the MSC-derived soluble factors hepatocyte growth factor (HGF) and prostaglandin E2in promoting wound healing and inhibiting apoptosis. Furthermore, this study translates these findings demonstrating an important role for HGF in the protective effects mediated by MSC in vivo in the bleomycin model. These findings support a targeted approach to enhancing MSC therapy for fibrotic disease and highlight the importance of timing of MSC therapy.
authors.affiliation: Institute of Immunology, Department of Biology, Maynooth University, Maynooth, County Kildare, Ireland.
authors.forename: Emer F
authors.initials: EF
authors.lastname: Cahill
authors.affiliation: Institute of Immunology, Department of Biology, Maynooth University, Maynooth, County Kildare, Ireland.
authors.forename: Helen
authors.initials: H
authors.lastname: Kennelly
authors.affiliation: Institute of Immunology, Department of Biology, Maynooth University, Maynooth, County Kildare, Ireland.
authors.forename: Fiona
authors.initials: F
authors.lastname: Carty
authors.affiliation: Institute of Immunology, Department of Biology, Maynooth University, Maynooth, County Kildare, Ireland.
authors.forename: Bernard P
authors.initials: BP
authors.lastname: Mahon
authors.affiliation: Institute of Immunology, Department of Biology, Maynooth University, Maynooth, County Kildare, Ireland karen.english@nuim.ie.
authors.forename: Karen
authors.initials: K
authors.lastname: English
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000633:toxicity; D017209:Apoptosis / Q000502:physiology; D001761:Bleomycin / Q000633:toxicity; D004195:Disease Models, Animal; D005260:Female; D055785:Gene Knockdown Techniques; D017228:Hepatocyte Growth Factor / Q000378:metabolism*; D054990:Idiopathic Pulmonary Fibrosis / Q000378:metabolism / Q000473:pathology*; D020287:In Situ Nick-End Labeling; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016133:Polymerase Chain Reaction
chemical_list: D000903:Antibiotics, Antineoplastic; D001761:Bleomycin; D017228:Hepatocyte Growth Factor
keywords: Antiapoptotic; Fibrosis; Hepatocyte growth factor; Mesenchymal stromal cell