title: Aberrant differentiation of fibroblast progenitors contributes to fibrosis in the aged murine heart: role of elevated circulating insulin levels.
abstract: 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.
authors.affiliation: Baylor College of Medicine, Department of Medicine, Division of Cardiovascular Sciences, One Baylor Plaza, Mail Station BCM620, Houston, Texas 77030, USA. cieslik@bcm.edu
authors.forename: Katarzyna A
authors.initials: KA
authors.lastname: Cieslik
authors.forename: JoAnn
authors.initials: J
authors.lastname: Trial
authors.forename: Signe
authors.initials: S
authors.lastname: Carlson
authors.forename: George E
authors.initials: GE
authors.lastname: Taffet
authors.forename: Mark L
authors.initials: ML
authors.lastname: Entman
mesh_terms: D000375:Aging; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects*; D002478:Cells, Cultured; D003094:Collagen / Q000096:biosynthesis; D024042:Collagen Type I / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology*; D005355:Fibrosis / Q000378:metabolism; D006321:Heart / Q000187:drug effects*; D007328:Insulin / Q000097:blood / Q000494:pharmacology*; D008297:Male; D059630:Mesenchymal Stem Cells / Q000166:cytology; D051379:Mice; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D024042:Collagen Type I; D007328:Insulin; D016212:Transforming Growth Factor beta; D003094:Collagen