A model for positive feedback control of the transformation of fibroblasts to myofibroblasts.

The phenotypic conversion of normal fibroblasts to myofibroblasts is central to normal wound healing and to pathological fibrosis that can occur in the heart and many other tissues. The transformation occurs in two stages. The first stage is driven mainly by mechanical changes such as increased stiffness of the heart due to hypertension and cellular contractility. The second stage requires both increasing stiffness and biochemical factors such as the growth factor, TGFβ. As more and more cells convert from weakly contractile fibroblasts to strongly contractile myofibroblasts, the stiffness of the ventricular muscle increases. We propose a simple model for the establishment of non-equilibrium steady states with different compositions of fibroblasts and myofibroblasts. Under some conditions a positive feedback loop resulting from the increasing stiffness caused by increasing numbers of myofibroblasts can produce a bifurcation between steady states with low and high myofibroblast content. We illustrate the large mechanical differences between normal fibroblasts and myofibroblasts with measurements in engineered tissue constructs.