TY - JOUR
T1 - Resident fibroblast lineages mediate pressure overload-induced cardiac fibrosis
AU - Moore-Morris, Thomas
AU - Guimarães-Camboa, Nuno
AU - Banerjee, Indroneal
AU - Zambon, Alexander C.
AU - Kisseleva, Tatiana
AU - Velayoudon, Aurélie
AU - Stallcup, William B.
AU - Gu, Yusu
AU - Dalton, Nancy D.
AU - Cedenilla, Marta
AU - Gomez-Amaro, Rafael
AU - Zhou, Bin
AU - Brenner, David A.
AU - Peterson, Kirk L.
AU - Chen, Ju
AU - Evans, Sylvia M.
PY - 2014/7/1
Y1 - 2014/7/1
N2 - 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.
AB - 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.
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U2 - 10.1172/JCI74783
DO - 10.1172/JCI74783
M3 - Article
C2 - 24937432
AN - SCOPUS:84903762014
SN - 0021-9738
VL - 124
SP - 2921
EP - 2934
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 7
ER -