title: Resident fibroblast lineages mediate pressure overload-induced cardiac fibrosis.
abstract: Activation and accumulation of cardiac fibroblasts, which result in excessive extracellular matrix deposition and consequent mechanical stiffness, myocyte uncoupling, and ischemia, are key contributors to heart failure progression. Recently, endothelial-to-mesenchymal transition (EndoMT) and the recruitment of circulating hematopoietic progenitors to the heart have been reported to generate substantial numbers of cardiac fibroblasts in response to pressure overload-induced injury; therefore, these processes are widely considered to be promising therapeutic targets. Here, using multiple independent murine Cre lines and a collagen1a1-GFP fusion reporter, which specifically labels fibroblasts, we found that following pressure overload, fibroblasts were not derived from hematopoietic cells, EndoMT, or epicardial epithelial-to-mesenchymal transition. Instead, pressure overload promoted comparable proliferation and activation of two resident fibroblast lineages, including a previously described epicardial population and a population of endothelial origin. Together, these data present a paradigm for the origins of cardiac fibroblasts during development and in fibrosis. Furthermore, these data indicate that therapeutic strategies for reducing pathogenic cardiac fibroblasts should shift from targeting presumptive EndoMT or infiltrating hematopoietically derived fibroblasts, toward common pathways upregulated in two endogenous fibroblast populations.
authors.forename: Thomas
authors.initials: T
authors.lastname: Moore-Morris
authors.forename: Nuno
authors.initials: N
authors.lastname: Guimarães-Camboa
authors.forename: Indroneal
authors.initials: I
authors.lastname: Banerjee
authors.forename: Alexander C
authors.initials: AC
authors.lastname: Zambon
authors.forename: Tatiana
authors.initials: T
authors.lastname: Kisseleva
authors.forename: Aurélie
authors.initials: A
authors.lastname: Velayoudon
authors.forename: William B
authors.initials: WB
authors.lastname: Stallcup
authors.forename: Yusu
authors.initials: Y
authors.lastname: Gu
authors.forename: Nancy D
authors.initials: ND
authors.lastname: Dalton
authors.forename: Marta
authors.initials: M
authors.lastname: Cedenilla
authors.forename: Rafael
authors.initials: R
authors.lastname: Gomez-Amaro
authors.forename: Bin
authors.initials: B
authors.lastname: Zhou
authors.forename: David A
authors.initials: DA
authors.lastname: Brenner
authors.forename: Kirk L
authors.initials: KL
authors.lastname: Peterson
authors.forename: Ju
authors.initials: J
authors.lastname: Chen
authors.forename: Sylvia M
authors.initials: SM
authors.lastname: Evans
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D001794:Blood Pressure; D006332:Cardiomegaly / Q000378:metabolism / Q000473:pathology; D019070:Cell Lineage; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism; D000090602:Collagen Type I, alpha 1 Chain; D004699:Endocardium / Q000378:metabolism / Q000473:pathology; D058750:Epithelial-Mesenchymal Transition; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D005355:Fibrosis; D020869:Gene Expression Profiling; D006333:Heart Failure / Q000209:etiology / Q000473:pathology* / Q000503:physiopathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009206:Myocardium / Q000378:metabolism / Q000473:pathology*; D010496:Pericardium / Q000378:metabolism / Q000473:pathology; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D015415:Biomarkers; D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; D011993:Recombinant Fusion Proteins