The Janus face of myofibroblasts in the remodeling heart

Cardiac fibrosis is a process that is associated with multiple forms of cardiac remodeling. There is an ongoing debate whether fibrosis is good or bad for cardiac function. On the one hand, deposition of extracellular matrix is indispensable for the wound healing in the injured heart; on the other hand, interstitial fibrosis can lead to stiffening of the ventricular wall and adverse remodeling. A common denominator of cardiac fibrosis is the appearance of myofibroblasts that possess smooth muscle-like contractile properties and can synthesize extracellular matrix. Traditionally, these cells were considered to merely derive from resident fibroblasts in the ventricular wall. However, recent insights suggest that myofibroblasts can originate from cell types as diverse as epicardial cells, resident mesenchymal stem cells and circulating fibrocytes. In this review, we will describe the origin(s) of the myofibroblasts in different forms of cardiac remodeling. We will also address the question whether specific mediators that are involved in the transdifferentiation of these myofibroblasts from their precursors can be identified. This would be of relevance in order to design specific interventions that would attenuate the adverse fibrotic deposition whilst preserving the favorable aspects of the fibrotic response.