title: Mesenchymal stem cell-derived inflammatory fibroblasts mediate interstitial fibrosis in the aging heart.
abstract: Pathologic fibrosis in the aging mouse heart is associated with dysregulated resident mesenchymal stem cells (MSC) arising from reduced stemness and aberrant differentiation into dysfunctional inflammatory fibroblasts. Fibroblasts derived from aging MSC secrete higher levels of 1) collagen type 1 (Col1) that directly contributes to fibrosis, 2) monocyte chemoattractant protein-1 (MCP-1) that attracts leukocytes from the blood and 3) interleukin-6 (IL-6) that facilitates transition of monocytes into myeloid fibroblasts. The transcriptional activation of these proteins is controlled via the farnesyltransferase (FTase)-Ras-Erk pathway. The intrinsic change in the MSC phenotype acquired by advanced age is specific for the heart since MSC originating from bone wall (BW-MSC) or fibroblasts derived from them were free of these defects. The potential therapeutic interventions other than clinically approved strategies based on findings presented in this review are discussed as well. This article is a part of a Special Issue entitled "Fibrosis and Myocardial Remodeling".
authors.affiliation: Division of Cardiovascular Sciences and the DeBakey Heart Center, Department of Medicine, Baylor College of Medicine, Houston, TX, United States.
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, TX, United States; Houston Methodist, Houston, TX, United States.
authors.forename: Mark L
authors.initials: ML
authors.lastname: Entman
authors.affiliation: Division of Cardiovascular Sciences and the DeBakey Heart Center, Department of Medicine, Baylor College of Medicine, Houston, TX, United States. Electronic address: cieslik@bcm.edu.
authors.forename: Katarzyna A
authors.initials: KA
authors.lastname: Cieslik
mesh_terms: D000375:Aging / Q000378:metabolism / Q000473:pathology*; D019883:Alkyl and Aryl Transferases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D044127:Epigenesis, Genetic; D005347:Fibroblasts / Q000166:cytology* / Q000378:metabolism; D005355:Fibrosis; D006801:Humans; D007249:Inflammation; D007328:Insulin / Q000235:genetics / Q000378:metabolism; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000378:metabolism; D051379:Mice; D022423:Myeloid Cells / Q000166:cytology* / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism / Q000473:pathology*; D015398:Signal Transduction; D020666:ras-GRF1 / Q000235:genetics / Q000378:metabolism
chemical_list: D016207:Cytokines; D007328:Insulin; C513039:RASGRF1 protein, human; D020666:ras-GRF1; D019883:Alkyl and Aryl Transferases; C064911:p21(ras) farnesyl-protein transferase
keywords: Aging; Fibrocyte; Inflammatory fibroblast; MSC; Myeloid fibroblasts; RasGrf1