Myofibroblasts and mechano-regulation of connective tissue remodelling

Abstract

Myofibroblasts are the predominant cell type that are present in granulation tissue of contracting wounds and fibrocontractive diseases, and are also present in some developing or normal adult tissues. The putative function of myofibroblasts is generating force and altering tissue tension. Myofibroblasts were initially characterized by the presence of microfilament bundles (stress fibres) that are not present in tissue fibroblasts. Two types of myofibroblasts can be characterized: proto-myofibroblasts, which contain stress fibres but lack α-smooth muscle (SM) actin, and differentiated myofibroblasts, which contain both stress fibres and α-SM actin. The formation and maintenance of the proto-myofibroblast is dependent on isometric tension applied onto a non-compliant substratum. The expression of α-SM actin that is characteristic of the differentiated myofibroblast is dependent on interaction of ED-A fibronectin with the cell surface and transforming growth factor β1 (TGF-β1). Myofibroblasts in granulation tissue and in in vitro contraction assays generate contractile force in response to certain SM agonists (such as endothelin). Increased expression of α-SM actin is directly correlated with increased force generation by myofibroblasts. We postulate a positive feedback loop in which tension facilitates TGF-β1 production and/or activation and α-SM actin expression. This, in turn, increases force production and tension development. Myofibroblast contraction is regulated by the level of myosin light chain phosphorylation and the key regulatory step seems to be activation of the Rho–Rho-kinase pathway, which results in the inhibition of myosin light chain phosphatase and increased myosin light chain phosphorylation and contraction. Tissue contraction (contracture) depends on collagen remodelling, a process that is dominated by extracellular-matrix reorganization under the mechanical control of myofibroblast contraction.