title: Modified mesenchymal stem cells using miRNA transduction alter lung injury in a bleomycin model.
abstract: Although different preclinical models have demonstrated a favorable role for bone marrow-derived mesenchymal stem cells (B-MSC) in preventing fibrosis, this protective effect is not observed with late administration of these cells, when fibrotic changes are consolidated. We sought to investigate whether the late administration of B-MSCs overexpressing microRNAs (miRNAs) let-7d (antifibrotic) or miR-154 (profibrotic) could alter lung fibrosis in a murine bleomycin model. Using lentiviral vectors, we transduced miRNAs (let-7d or miR-154) or a control sequence into human B-MSCs. Overexpression of let-7d or miR-154 was associated with changes in the mesenchymal properties of B-MSCs and in their cytokine expression. Modified B-MSCs were intravenously administered to mice atday 7after bleomycin instillation, and the mice were euthanized atday 14Bleomycin-injured animals that were treated with let-7d cells were found to recover quicker from the initial weight loss compared with the other treatment groups. Interestingly, animals treated with miR-154 cells had the lowest survival rate. Although a slight reduction in collagen mRNA levels was observed in lung tissue from let-7d mice, no significant differences were observed in Ashcroft score and OH-proline. However, the distinctive expression in cytokines and CD45-positive cells in the lung suggests that the differential effects observed in both miRNA mice groups were related to an effect on the immunomodulation function. Our results establish the use of miRNA-modified mesenchymal stem cells as a potential future research in lung fibrosis.
authors.affiliation: Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.|The Dorothy P. and Richard P. Simmons Center for Interstitial Lung Disease, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.|The Shraga Segal Department of Microbiology, Immunology and Genetics, Faculty of Health Sciences, Ben Gurion University of the Negev, Beer-Sheva, Israel.|Section of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, Yale University, New Haven, Connecticut.
authors.forename: Luai
authors.initials: L
authors.lastname: Huleihel
authors.affiliation: Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.|The Dorothy P. and Richard P. Simmons Center for Interstitial Lung Disease, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.|Servei de Pneumologia, Hospital Clínic, August Pi i Sunyer Biomedical Research Institute, Universitat de Barcelona, Barcelona, Spain.|Centro de Investigación Biomedica En Red-Enfermedades Respiratorias, Institut Investigacions Biomèdiques, August Pi i Sunyer Biomedical Research Institute, Barcelona, Spain; and.
authors.forename: Jacobo
authors.initials: J
authors.lastname: Sellares
authors.affiliation: Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.|The Dorothy P. and Richard P. Simmons Center for Interstitial Lung Disease, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.
authors.forename: Nayra
authors.initials: N
authors.lastname: Cardenes
authors.affiliation: Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.|The Dorothy P. and Richard P. Simmons Center for Interstitial Lung Disease, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.
authors.forename: Diana
authors.initials: D
authors.lastname: Álvarez
authors.affiliation: Centro de Investigación Biomedica En Red-Enfermedades Respiratorias, Institut Investigacions Biomèdiques, August Pi i Sunyer Biomedical Research Institute, Barcelona, Spain; and.
authors.forename: Rosa
authors.initials: R
authors.lastname: Faner
authors.affiliation: Section of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, Yale University, New Haven, Connecticut.
authors.forename: Koji
authors.initials: K
authors.lastname: Sakamoto
authors.affiliation: Section of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, Yale University, New Haven, Connecticut.
authors.forename: Guoying
authors.initials: G
authors.lastname: Yu
authors.affiliation: Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.
authors.forename: Maria G
authors.initials: MG
authors.lastname: Kapetanaki
authors.affiliation: Section of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, Yale University, New Haven, Connecticut.
authors.forename: Naftali
authors.initials: N
authors.lastname: Kaminski
authors.affiliation: Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania; rojasm@upmc.edu.|The Dorothy P. and Richard P. Simmons Center for Interstitial Lung Disease, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.|McGowan Institute for Regenerative Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
authors.forename: Mauricio
authors.initials: M
authors.lastname: Rojas
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D001761:Bleomycin; D001854:Bone Marrow Cells / Q000166:cytology; D003094:Collagen / Q000235:genetics / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D017493:Leukocyte Common Antigens / Q000378:metabolism; D055370:Lung Injury / Q000378:metabolism* / Q000628:therapy*; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016019:Survival Analysis; D014161:Transduction, Genetic; D014162:Transfection; D015431:Weight Loss
chemical_list: D015415:Biomarkers; D016207:Cytokines; D015850:Interleukin-6; C561122:MIRN154 microRNA, human; D035683:MicroRNAs; D012333:RNA, Messenger; C487931:mirnlet7 microRNA, human; D001761:Bleomycin; D003094:Collagen; D017493:Leukocyte Common Antigens
keywords: bone marrow-derived mesenchymal stem cells; immunomodulation; lung fibrosis; microRNA