Cardiac fibroblasts: from development to heart failure

Abstract

Cardiac fibroblasts are a major cell population of the heart and are characterized by their capacity to produce extracellular matrix (ECM). In hearts subjected to pressure overload, excessive fibroblast accumulation is responsible for fibrosis of the myocardium, a major clinical issue. Hence, understanding mechanisms generating fibroblasts in this context has become a key question in the cardiovascular field. Recent studies now point to the activation of resident fibroblasts as the underlying cause of fibrosis. However, de novo generation of fibroblasts from endothelium and circulating hematopoietic cells has also been proposed to significantly contribute to fibrosis. Here, we discuss the latest findings on fibroblast origins, with a particular emphasis on the pressure overload model, and the implication of these findings for the development of anti-fibrotic therapies that are currently lacking.

Figure 1

Lineages giving rise to cardiac fibroblasts during embryonic development. Illustration of an E9.5 embryo showing the myocardium with its inner endocardium, the proepicardial organ and migrating neural crest cells. Fibroblasts derived from the AVC cushion (orange) first invade the septum at E12.5. Subsequently, epicardial EMT generates fibroblasts (green) that invade the free walls by E14.5. In adult heart, endothelially derived fibroblasts are found most abundantly in the septum, whereas epicardially derived fibroblasts populate the free walls.

Figure 2

Interstitial and perivascular fibrosis results from the proliferation of resident fibroblast lineages. Following pressure overload, local signaling from myocytes and non-myocytes, including vascular cells and immune cells, promotes PDGFRα⁺;Collagen1a1-GFP⁺ fibroblast proliferation throughout the myocardium. Several markers have specifically been associated with fibroblasts in interstitial and perivascular fibrotic lesions, but are not expressed by all fibroblasts in these areas (+/−).