50 Years of Myofibroblasts: How the Myofibroblast Concept Evolved.

Myofibroblasts are key cells in mediating normal wound contraction and promoting connective tissue deformations characteristic of fibrosis and scarring. Five decades ago, myofibroblasts were discovered in electron micrographs of wound granulation tissue as fibroblastic cells containing microfilaments that are organized in bundles like those present in smooth muscle. The contractile function of myofibroblasts was demonstrated by measuring the contraction of strips of granulation tissue in response to smooth muscle agonists and in cell culture. Although formation of contractile bundles already defines the myofibroblast, neo-expression of α-smooth muscle actin (α-SMA) in fibroblastic cells has become the most widely used myofibroblast marker. Because α-SMA incorporation into stress fibers mediates enhanced fibroblast contraction, it has been proposed and successfully tested as a drug target in therapeutic approaches to reduce tissue contractures. Other anti-fibrosis strategies target growth factor-, extracellular matrix-, and mechanical stress-induced pathways of myofibroblast activation from various precursors or aim to induce myofibroblast apoptosis. To understand the involved mechanisms of myofibroblast formation and function, critical experimental tools and animal models have been developed, which are made available in this collection of protocols by experts in the field.