Resident fibroblast lineages mediate pressure overload-induced cardiac fibrosis

Thomas Moore-Morris, Nuno Guimarães-Camboa, Indroneal Banerjee, Alexander C. Zambon, Tatiana Kisseleva, Aurélie Velayoudon, William B. Stallcup, Yusu Gu, Nancy D. Dalton, Marta Cedenilla, Rafael Gomez-Amaro, Bin Zhou, David A. Brenner, Kirk L. Peterson, Ju Chen, Sylvia M. Evans

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)2921-2934
Number of pages14
JournalJournal of Clinical Investigation
Volume124
Issue number7
DOIs
StatePublished - Jul 1 2014

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Fibrosis
Fibroblasts
Pressure
Population
Epithelial-Mesenchymal Transition
Muscle Cells
Extracellular Matrix
Ischemia
Endothelial Cells
Heart Failure
Wounds and Injuries
Therapeutics

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Moore-Morris, T., Guimarães-Camboa, N., Banerjee, I., Zambon, A. C., Kisseleva, T., Velayoudon, A., ... Evans, S. M. (2014). Resident fibroblast lineages mediate pressure overload-induced cardiac fibrosis. Journal of Clinical Investigation, 124(7), 2921-2934. https://doi.org/10.1172/JCI74783

Resident fibroblast lineages mediate pressure overload-induced cardiac fibrosis. / Moore-Morris, Thomas; Guimarães-Camboa, Nuno; Banerjee, Indroneal; Zambon, Alexander C.; Kisseleva, Tatiana; Velayoudon, Aurélie; Stallcup, William B.; Gu, Yusu; Dalton, Nancy D.; Cedenilla, Marta; Gomez-Amaro, Rafael; Zhou, Bin; Brenner, David A.; Peterson, Kirk L.; Chen, Ju; Evans, Sylvia M.

In: Journal of Clinical Investigation, Vol. 124, No. 7, 01.07.2014, p. 2921-2934.

Research output: Contribution to journalArticle

Moore-Morris, T, Guimarães-Camboa, N, Banerjee, I, Zambon, AC, Kisseleva, T, Velayoudon, A, Stallcup, WB, Gu, Y, Dalton, ND, Cedenilla, M, Gomez-Amaro, R, Zhou, B, Brenner, DA, Peterson, KL, Chen, J & Evans, SM 2014, 'Resident fibroblast lineages mediate pressure overload-induced cardiac fibrosis', Journal of Clinical Investigation, vol. 124, no. 7, pp. 2921-2934. https://doi.org/10.1172/JCI74783
Moore-Morris T, Guimarães-Camboa N, Banerjee I, Zambon AC, Kisseleva T, Velayoudon A et al. Resident fibroblast lineages mediate pressure overload-induced cardiac fibrosis. Journal of Clinical Investigation. 2014 Jul 1;124(7):2921-2934. https://doi.org/10.1172/JCI74783
Moore-Morris, Thomas ; Guimarães-Camboa, Nuno ; Banerjee, Indroneal ; Zambon, Alexander C. ; Kisseleva, Tatiana ; Velayoudon, Aurélie ; Stallcup, William B. ; Gu, Yusu ; Dalton, Nancy D. ; Cedenilla, Marta ; Gomez-Amaro, Rafael ; Zhou, Bin ; Brenner, David A. ; Peterson, Kirk L. ; Chen, Ju ; Evans, Sylvia M. / Resident fibroblast lineages mediate pressure overload-induced cardiac fibrosis. In: Journal of Clinical Investigation. 2014 ; Vol. 124, No. 7. pp. 2921-2934.
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