TY - JOUR
T1 - Aberrant differentiation of fibroblast progenitors contributes to fibrosis in the aged murine heart
T2 - Role of elevated circulating insulin levels
AU - Cieslik, Katarzyna A.
AU - Trial, Jo Ann
AU - Carlson, Signe
AU - Taffet, George
AU - Entman, Mark L.
N1 - Copyright:
Copyright 2013 Elsevier B.V., All rights reserved.
PY - 2013/4
Y1 - 2013/4
N2 - With age, the collagen content of the heart increases, leading to interstitial fibrosis. We have shown that CD44pos 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.
AB - With age, the collagen content of the heart increases, leading to interstitial fibrosis. We have shown that CD44pos 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.
KW - Collagen
KW - Mesenchymal stem cell
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U2 - 10.1096/fj.12-220145
DO - 10.1096/fj.12-220145
M3 - Article
C2 - 23303205
AN - SCOPUS:84875755735
SN - 1530-6860
VL - 27
SP - 1761
EP - 1771
JO - FASEB Journal
JF - FASEB Journal
IS - 4
ER -