title: Therapeutic benefits of young, but not old, adipose-derived mesenchymal stem cells in a chronic mouse model of bleomycin-induced pulmonary fibrosis.
abstract: The observation that pulmonary inflammatory lesions and bleomycin (BLM)-induced pulmonary fibrosis spontaneously resolve in young mice, whereas remaining irreversible in aged mice suggests that impairment of pulmonary regeneration and repair is associated with aging. Because mesenchymal stem cells (MSCs) may promote repair after injury, we postulated that differences in MSCs from aged mice may underlie postinjury fibrosis in aging. The potential for young-donor MSCs to inhibit BLM-induced pulmonary fibrosis in aged male mice (>22 months) has not been studied. Adipose-derived MSCs (ASCs) from young (4 months) and old (22 months) male mice were infused 1 day after intratracheal BLM administration. At 21-day sacrifice, aged BLM mice demonstrated lung fibrosis by Ashcroft score, collagen content, and α(v)-integrin messenger RNA (mRNA) expression. Lung tissue from aged BLM mice receiving young ASCs exhibited decreased fibrosis, matrix metalloproteinase (MMP)-2 activity, oxidative stress, and markers of apoptosis vs BLM controls. Lung mRNA expression of tumor necrosis factor-alpha was also decreased in aged BLM mice receiving young-donor ASCs vs BLM controls. In contrast, old-donor ASC treatment in aged BLM mice did not reduce fibrosis and related markers. On examination of the cells, young-donor ASCs had decreased mRNA expression of MMP-2, insulin-like growth factor (IGF) receptor, and protein kinase B (AKT) activation compared with old-donor ASCs. These results show that the BLM-induced pulmonary fibrosis in aged mice could be blocked by young-donor ASCs and that the mechanisms involve changes in collagen turnover and markers of inflammation.
authors.affiliation: Department of Surgery, Leonard M. Miller School of Medicine, University of Miami, Miami, Fla.
authors.forename: Jun
authors.initials: J
authors.lastname: Tashiro
authors.affiliation: Department of Surgery, Leonard M. Miller School of Medicine, University of Miami, Miami, Fla.
authors.forename: Sharon J
authors.initials: SJ
authors.lastname: Elliot
authors.affiliation: Department of Surgery, Leonard M. Miller School of Medicine, University of Miami, Miami, Fla.
authors.forename: David J
authors.initials: DJ
authors.lastname: Gerth
authors.affiliation: Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, Department of Medicine, Leonard M. Miller School of Medicine, University of Miami, Miami, Fla.
authors.forename: Xiaomei
authors.initials: X
authors.lastname: Xia
authors.affiliation: Department of Surgery, Leonard M. Miller School of Medicine, University of Miami, Miami, Fla.
authors.forename: Simone
authors.initials: S
authors.lastname: Pereira-Simon
authors.affiliation: Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, Department of Medicine, Leonard M. Miller School of Medicine, University of Miami, Miami, Fla.
authors.forename: Rhea
authors.initials: R
authors.lastname: Choi
authors.affiliation: Department of Surgery, Leonard M. Miller School of Medicine, University of Miami, Miami, Fla.
authors.forename: Paola
authors.initials: P
authors.lastname: Catanuto
authors.affiliation: Division of Pediatric Pulmonology, Department of Pediatrics, Leonard M. Miller School of Medicine, University of Miami, Miami, Fla.
authors.forename: Shahriar
authors.initials: S
authors.lastname: Shahzeidi
authors.affiliation: Department of Medicine, Herbert Wertheim College of Medicine, Florida International University, Miami, Fla.
authors.forename: Rebecca L
authors.initials: RL
authors.lastname: Toonkel
authors.affiliation: Department of Surgery, Leonard M. Miller School of Medicine, University of Miami, Miami, Fla.
authors.forename: Rahil H
authors.initials: RH
authors.lastname: Shah
authors.affiliation: Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY.
authors.forename: Fadi
authors.initials: F
authors.lastname: El Salem
authors.affiliation: Department of Surgery, Leonard M. Miller School of Medicine, University of Miami, Miami, Fla; Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, Department of Medicine, Leonard M. Miller School of Medicine, University of Miami, Miami, Fla; Division of Pediatric Pulmonology, Department of Pediatrics, Leonard M. Miller School of Medicine, University of Miami, Miami, Fla. Electronic address: mglassbe@med.miami.edu.
authors.forename: Marilyn K
authors.initials: MK
authors.lastname: Glassberg
mesh_terms: D000273:Adipose Tissue / Q000166:cytology*; D000367:Age Factors; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D001761:Bleomycin / Q000633:toxicity*; D004195:Disease Models, Animal; D004789:Enzyme Activation; D020287:In Situ Nick-End Labeling; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology*; D051379:Mice; D008810:Mice, Inbred C57BL; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000628:therapy*
chemical_list: D015415:Biomarkers; D001761:Bleomycin; D051057:Proto-Oncogene Proteins c-akt; D020778:Matrix Metalloproteinase 2