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Aberrant differentiation of fibroblast progenitors contributes to fibrosis in the aged murine heart: role of elevated circulating insulin levels
Author(s) -
Cieslik Katarzyna A.,
Trial JoAnn,
Carlson Signe,
Taffet George E.,
Entman Mark L.
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.12-220145
Subject(s) - insulin , fibrosis , endocrinology , fibroblast , medicine , mesenchymal stem cell , myocardial fibrosis , biology , cardiac fibrosis , inflammation , microbiology and biotechnology , in vitro , biochemistry
With age, the collagen content of the heart increases, leading to interstitial fibrosis. We have shown that CD44 pos fibroblasts derived from aged murine hearts display reduced responsiveness to TGF‐β but, paradoxically, have increased collagen expression in vivo and in vitro. We postulated that this phenomenon was due to the defect in mesenchymal stem cell (MSC) differentiation in a setting of elevated circulating insulin levels and production that we observed in aging mice. We discovered that cultured fibroblasts derived from aged but not young cardiac MSCs of nonhematopoietic lineage displayed increased basal and insulin‐induced (1 nM) collagen expression (2‐fold), accompanied by increased farnesyltransferase (FTase) and Erk activities. In a quest for a possible mechanism, we found that a chronic pathophysiologic insulin concentration (1 nM) caused abnormal fibroblast differentiation of MSCs isolated from young hearts. Fibroblasts derived from these MSCs responded to insulin by elevating collagen expression as seen in untreated aged fibroblast cultures, suggesting a causal link between increased insulin levels and defective MSC responses. Here we report an insulin‐dependent pathway that specifically targets collagen type I transcriptional activation leading to a unique mechanism of fibrosis that is TGF‐β and inflammation‐independent in the aged heart.—Cieslik, K. A., Trial, J., Carlson, S., Taffet, G. E., Entman, M. L. Aberrant differentiation of fibroblast progenitors contributes to fibrosis in the aged murine heart: role of elevated circulating insulin levels. FASEB J. 27, 1761–1771 (2013). www.fasebj.org