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.

Developmental origin and lineage plasticity of endogenous cardiac stem cells

“…An early CRE-based lineage-tracing experiment suggested that a subset of cardiac stromal fibroblasts arise de novo via endothelial-tomesenchymal transition (EndMT) from adult endothelial cells (Zeisberg et al, 2007). However, more recent lineage-tracing studies have shown that the proliferation and expansion of resident fibroblasts during cardiac hypertrophy accounts for almost all cardiac fibroblasts (Ali et al, 2014;Moore-Morris et al, 2014). Around 80% of the fibroblasts had their origins in the epicardium, with the remainder derived from the endocardium via EndMT (Ali et al, 2014;Moore-Morris et al, 2014), although a limited number of adult fibroblasts in the right atrium and outflow tract region might derive from neural crest cells (Ali et al, 2014).…”

“…However, more recent lineage-tracing studies have shown that the proliferation and expansion of resident fibroblasts during cardiac hypertrophy accounts for almost all cardiac fibroblasts (Ali et al, 2014;Moore-Morris et al, 2014). Around 80% of the fibroblasts had their origins in the epicardium, with the remainder derived from the endocardium via EndMT (Ali et al, 2014;Moore-Morris et al, 2014), although a limited number of adult fibroblasts in the right atrium and outflow tract region might derive from neural crest cells (Ali et al, 2014). Importantly, the developmental origin of adult stromal fibroblasts does not appear to affect the cellular fibroblast phenotype, transcriptional profile, response to apoptotic stimuli or proliferation rate (Ali et al, 2014).…”

Targeting cardiac fibroblasts: The pressure is on

“…Here, we discuss limitations of these studies arising from markers utilized for cardiac fibroblasts, as well as our recently reported findings on cardiac fibroblast markers and origins 3 and their clinical impact.…”

“…1 However, our lineage tracing of adult endothelium with an inducible endothelial specific Cre, VEcadherin-CreERT2 did not reveal evidence that EndoMT had occurred. 3 A previous study performed to assess the occurrence of EndoMT utilized an endothelial Cre, Tie1-Cre, which labels both endothelial and haematopoietic lineages.…”

“…1 Utilizing a pan-haematopoietic Cre, Vav-Cre, in conjunction with Collagen1a1-GFP and PDGFRa, we could not find evidence for any fibroblasts of haematopoietic origin in fibrotic lesions following pressure overload. 3 Fibroblasts have been shown to derive from epicardial EMT during midgestation, although other developmental origins have not been excluded. 2 Using epicardial-specific Cre drivers, we observed that most, but not all, cardiac fibroblasts were of epicardial origin.…”