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

Jun Tashiro, Sharon J. Elliot, David J. Gerth, Xiaomei Xia, Simone Pereira-Simon, Rhea Choi, Paola Catanuto, Shahriar Shahzeidi, Rebecca L. Toonkel, Rahil H. Shah, Fadi El Salem, Marilyn K. Glassberg

Research output: Contribution to journalArticle

34 Scopus citations

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 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.

Original languageEnglish (US)
Pages (from-to)554-567
Number of pages14
JournalTranslational Research
Volume166
Issue number6
DOIs
StatePublished - Dec 1 2015

ASJC Scopus subject areas

  • Public Health, Environmental and Occupational Health
  • Biochemistry, medical
  • Physiology (medical)

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    Tashiro, J., Elliot, S. J., Gerth, D. J., Xia, X., Pereira-Simon, S., Choi, R., Catanuto, P., Shahzeidi, S., Toonkel, R. L., Shah, R. H., El Salem, F., & Glassberg, M. K. (2015). Therapeutic benefits of young, but not old, adipose-derived mesenchymal stem cells in a chronic mouse model of bleomycin-induced pulmonary fibrosis. Translational Research, 166(6), 554-567. https://doi.org/10.1016/j.trsl.2015.09.004