Evasion of apoptosis by myofibroblasts: a hallmark of fibrotic diseases
- PMID: 31792399
- PMCID: PMC7913072
- DOI: 10.1038/s41584-019-0324-5
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.
Conflict of interest statement
Competing interests
D.L. declares that he has received research funding from Boehringer Ingelheim, Indalo Therapeutics and Unity Biotechnology. D.L. also has a financial interest in Mediar Therpeutics, which is developing treatments for organ fibrosis. D.L.’s interests were reviewed and are managed by MGH and Partners HealthCare in accordance with their conflict of interest policies. B.H. declares no competing interests.
Figures
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