Origin of Developmental Precursors Dictates the Pathophysiologic Role of Cardiac Fibroblasts

Fibroblasts in the heart play a critical function in the secretion and modulation of extracellular matrix critical for optimal cellular architecture and mechanical stability required for its mechanical function. Fibroblasts are also intimately involved in both adaptive and nonadaptive responses to cardiac injury. Fibroblasts provide the elaboration of extracellular matrix and, as myofibroblasts, are responsible for cross-linking this matrix to form a mechanically stable scar after myocardial infarction. By contrast, during heart failure, fibroblasts secrete extracellular matrix, which manifests itself as excessive interstitial fibrosis that may mechanically limit cardiac function and distort cardiac architecture (adverse remodeling). This review examines the hypothesis that fibroblasts mediating scar formation and fibroblasts mediating interstitial fibrosis arise from different cellular precursors and in response to different autocoidal signaling cascades. We demonstrate that fibroblasts which generate scars arise from endogenous mesenchymal stem cells, whereas those mediating adverse remodeling are of myeloid origin and represent immunoinflammatory dysregulation.