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Therapeutic benefits of young, but not old, adipose-derived mesenchymal stem cells in a chronic mouse model of bleomycin-induced pulmonary fibrosis

Published:September 17, 2015DOI:https://doi.org/10.1016/j.trsl.2015.09.004
      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 αv-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.

      Abbreviations:

      IPF (idiopathic pulmonary fibrosis), BLM (bleomycin), MMP (matrix metalloproteinase), MSC (mesenchymal stem cell), ASC (adipose-derived mesenchymal stem cell), BM-MSC (bone marrow-derived mesenchymal stem cell), oASC (old-donor ASC), yASC (young-donor ASC), AKT (protein kinase B), TGF-β (transforming growth factor-β), TNF-α (tumor necrosis factor-alpha), LPS (lipopolysaccharide), PE (phycoerythrin), FITC (fluorescein isothiocyanate), VEGF (vascular endothelial growth factor), IGF (insulin-like growth factor), PCR (polymerase chain reaction), pAKT (phosphorylated AKT), TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling), ROS (reactive oxygen species), IgG (immunoglobulin G), ANOVA (analysis of variance), FACS (fluorescence activated cell sorting), ARDS (acute respiratory distress syndrome)
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      Biography

      Jun Tashiro, MD, MPH, is a research fellow in the Department of Surgery at the University of Miami Miller School of Medicine. His article is based on a presentation given at the 2015 Combined Annual Meeting of the Central Society for Clinical and Translational Research and the Midwestern Section American Federation for Medical Research, held in Chicago, Ill. Dr. Tashiro is interested in optimizing mesenchymal stem cell-based therapy and identifying its most active components in the setting of pulmonary fibrosis and other processes mediated by inflammation.