The myofibroblast in wound healing and fibrosis: answered and unanswered questions

Abstract

The discovery of the myofibroblast has allowed definition of the cell responsible for wound contraction and for the development of fibrotic changes. This review summarizes the main features of the myofibroblast and the mechanisms of myofibroblast generation. Myofibroblasts originate from a variety of cells according to the organ and the type of lesion. The mechanisms of myofibroblast contraction, which appear clearly different to those of smooth muscle cell contraction, are described. Finally, we summarize the possible strategies in order to reduce myofibroblast activities and thus influence several pathologies, such as hypertrophic scars and organ fibrosis.

Keywords: Myofibroblast; hypertrophic scars; mechanotransduction; myofibroblast contraction; myofibroblast generation; organ fibroses.

Figure 1.. Mechanical activation of TGF-β1

In normal connective tissue, loosely arranged collagen protects resident fibroblasts and latent transforming growth factor (TGF)-β1 complexes from being strained with the extracellular matrix (ECM). Fibroblasts in normal tissue do not express or present the integrin receptors that bind and activate latent TGF-β1. During tissue repair and in organ fibrosis, activated myofibroblasts express αv integrins that connect the contractile actin/myosin cytoskeleton to latent TGF-β1. The accumulation of collagen and its excessive remodeling (crosslinking) by these myofibroblasts result in denser and straighter ECM fibers, which leads to overall higher tissue stiffness. Because ECM fibers are straighter, even smaller strains applied to the fibrotic ECM externally, or by residing myofibroblasts, will be sufficient for the release of active TGF-β1 (modified from Hinz B and Suki B [2016] Does breathing amplify fibrosis? Editorial on 21).