title: Mesenchymal stem cell-derived inflammatory fibroblasts promote monocyte transition into myeloid fibroblasts via an IL-6-dependent mechanism in the aging mouse heart.
abstract: Fibrosis in the old mouse heart arises partly as a result of aberrant mesenchymal fibroblast activation. We have previously shown that endogenous mesenchymal stem cells (MSCs) in the aged heart are markedly resistant to TGF-β signaling. Fibroblasts originating from these MSCs retain their TGF-β unresponsiveness and become inflammatory. In current studies, we found that these inflammatory fibroblasts secreted higher levels of IL-6 (3-fold increase, P < 0.05) when compared with fibroblasts derived from the young hearts. Elevated IL-6 levels in fibroblasts derived from old hearts arose from up-regulated expression of Ras protein-specific guanine nucleotide releasing factor 1 (RasGrf1), a Ras activator (5-fold, P < 0.01). Knockdown of RasGrf1 by gene silencing or pharmacologic inhibition of farnesyltransferase (FTase) or ERK caused reduction of IL-6 mRNA (more than 65%, P < 0.01) and decreased levels of secreted IL-6 (by 44%, P < 0.01). In vitro, IL-6 markedly increased monocyte chemoattractant protein-1-driven monocyte-to-myeloid fibroblast formation after transendothelial migration (TEM; 3-fold, P < 0.01). In conclusion, abnormal expression of RasGrf1 promoted production of IL-6 by mesenchymal fibroblasts in the old heart. Secreted IL-6 supported conversion of monocyte into myeloid fibroblasts. This process promotes fibrosis and contributes to the diastolic dysfunction in the aging heart.
authors.affiliation: Division of Cardiovascular Sciences and the DeBakey Heart Center, Department of Medicine, Baylor College of Medicine, Houston, Texas, USA cieslik@bcm.edu.
authors.forename: Katarzyna A
authors.initials: KA
authors.lastname: Cieslik
authors.affiliation: Division of Cardiovascular Sciences and the DeBakey Heart Center, Department of Medicine, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: JoAnn
authors.initials: J
authors.lastname: Trial
authors.affiliation: Division of Cardiovascular Sciences and the DeBakey Heart Center, Department of Medicine, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Mark L
authors.initials: ML
authors.lastname: Entman
mesh_terms: D000375:Aging / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D005347:Fibroblasts / Q000378:metabolism* / Q000502:physiology; D005355:Fibrosis / Q000378:metabolism / Q000473:pathology; D006321:Heart / Q000503:physiopathology; D007249:Inflammation / Q000378:metabolism* / Q000473:pathology; D015850:Interleukin-6 / Q000378:metabolism*; D008297:Male; D059630:Mesenchymal Stem Cells / Q000378:metabolism* / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000378:metabolism* / Q000502:physiology; D022423:Myeloid Cells / Q000378:metabolism* / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D015850:Interleukin-6; D016212:Transforming Growth Factor beta; C577686:interleukin-6, mouse
keywords: RasGrf1; fibrosis; transendothelial migration