Sorting out where fibroblasts come from.

H eart failure is the primary cause of adult mortality in the Western world, affecting 1% to 2% of the population, including ≤10% of people >70 1. Several disease settings, including coronary artery disease, hypertension, diabetes melli-tus, and hypertrophic cardiomyopathy, promote a maladaptive response characterized by myocyte hypertrophy and fibrosis. The latter refers to excessive extracellular matrix deposition that causes myocardial stiffening characteristic of heart failure. Cardiac fibroblasts are the primary cell type responsible for extracellular matrix remodeling during development and in disease. In a pathological context, activation and accumulation of fibroblasts perturb normal deposition and degradation of ex-tracellular matrix components, notably of collagen type I 2 and causes formation of rigid fibrotic lesions within myocardium. Hence, identifying mechanisms responsible for fibroblast accumulation in the failing heart represents a key issue for development of effective antifibrotic therapies. Recent studies have proposed that endothelial-to-mesen-chymal transition (EndoMT) and recruitment of circulating progenitors generate fibroblasts responsible for cardiac fibro-sis 3,4 A key marker used to identify cardiac fibroblasts in these studies was fibroblast-specific protein 1 5 that has been recently shown to be expressed by other cell types in the heart, including immune cells. 6 Many of these studies acknowledge that resident fibroblast populations are also engaged in the process of remodeling, but some have implied that these nonresident cell populations are more pathogenic or the " bad guys, " suggesting that these cells contribute significantly to inflammation and matrix production under pathological conditions. 7,8 Several markers are currently used to identify cardiac fi-broblasts, including discoidin domain receptor family member 2, 9 vimentin, fibroblast-specific protein 1, 3 and Thy1. 10 However, these markers are also expressed by other cell types. Immunostaining against secreted extracellular matrix proteins such as collagen type I and periostin is also commonly used to identify fibroblasts but identification of the producing cell after deposition of the matrix protein is difficult, and vascu-lar smooth muscle cells also produce these proteins to some extent. Recently, more specific cardiac fibroblast markers have been demonstrated, including platelet-derived growth factor receptor α and transcription factor 21. Nonetheless, it seems that the adult cardiac fibroblast population has heterogeneous gene expression, and there may not be any single marker that is uniquely and uniformly expressed. Identifying marker combinations enabling specific labeling of cardiac fi-broblasts in healthy and diseased hearts represents a key challenge in the cardiac pathology field. During development the proepicardium contributes noncar-diac mesenchymal progenitors …