Resident fibroblast lineages mediate pressure overload–induced cardiac fibrosis

TLDR

Cardiac fibroblast activation and accumulation drive fibrosis, stiffness, and heart failure, and pressure overload has been thought to generate fibroblasts via EndoMT and hematopoietic progenitor recruitment. Using lineage tracing, the study shows that pressure overload induces proliferation of resident epicardial and endothelial‑derived fibroblast lineages, rather than hematopoietic or EndoMT sources, implying therapies should target common pathways in these endogenous populations.

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.