Evasion of apoptosis by myofibroblasts: a hallmark of fibrotic diseases

Abstract

Organ fibrosis is a lethal outcome of autoimmune rheumatic diseases such as systemic sclerosis. Myofibroblasts are scar-forming cells that are ultimately responsible for the excessive synthesis, deposition and remodelling of extracellular matrix proteins in fibrosis. Advances have been made in our understanding of the mechanisms that keep myofibroblasts in an activated state and control myofibroblast functions. However, the mechanisms that help myofibroblasts to persist in fibrotic tissues remain poorly understood. Myofibroblasts evade apoptosis by activating molecular mechanisms in response to pro-survival biomechanical and growth factor signals from the fibrotic microenvironment, which can ultimately lead to the acquisition of a senescent phenotype. Growing evidence suggests that myofibroblasts and senescent myofibroblasts, rather than being resistant to apoptosis, are actually primed for apoptosis owing to concomitant activation of cell death signalling pathways; these cells are poised to apoptose when survival pathways are inhibited. This knowledge of apoptotic priming has paved the way for new therapies that trigger apoptosis in myofibroblasts by blocking pro-survival mechanisms, target senescent myofibroblast for apoptosis or promote the reprogramming of myofibroblasts into scar-resolving cells. These novel strategies are not only poised to prevent progressive tissue scarring, but also have the potential to reverse established fibrosis and to regenerate chronically injured tissues. Myofibroblasts are important mediators of wound healing but can also perpetuate fibrosis in diseases such as systemic sclerosis by evading apoptosis. Therapeutic targeting of the survival mechanisms used by these cells in fibrotic disease holds promise for the reversal of fibrosis. Organ fibrosis is a lethal outcome of autoimmune rheumatic diseases such as systemic sclerosis (SSc). Myofibroblasts are scar-forming cells that are responsible for the excessive synthesis, deposition and remodelling of extracellular matrix proteins in SSc. Persistent myofibroblast activity leads to progressive tissue fibrosis and distortion of the normal tissue architecture, resulting in organ failure and, ultimately, in death. The termination of myofibroblast activity is suppressed in fibrotic disease by biomechanical and biochemical cues, which assist myofibroblast escape from apoptosis, thereby halting their elimination. Evasion of apoptosis results in persistent myofibroblast activation and/or the differentiation of myofibroblasts into a pro-fibrotic or pro-inflammatory senescent phenotype, thereby preventing fibrosis resolution. Targeting myofibroblast apoptosis and reprogramming these cells to become scar-resolving cells are emerging as novel therapeutic strategies to reverse established fibrosis.