The myofibroblast, multiple origins for major roles in normal and pathological tissue repair

Abstract

Myofibroblasts differentiate, invade and repair injured tissues by secreting and organizing the extracellular matrix and by developing contractile forces. When tissues are damaged, tissue homeostasis must be re-established, and repair mechanisms have to rapidly provide harmonious mechanical tissue organization, a process essentially supported by (myo)fibroblasts. Under physiological conditions, the secretory and contractile activities of myofibroblasts are terminated when the repair is complete (scar formation) but the functionality of the tissue is only rarely perfectly restored. At the end of the normal repair process, myofibroblasts disappear by apoptosis but in pathological situations, myofibroblasts likely remain leading to excessive scarring. Myofibroblasts originate from different precursor cells, the major contribution being from local recruitment of connective tissue fibroblasts. However, local mesenchymal stem cells, bone marrow-derived mesenchymal stem cells and cells derived from an epithelial-mesenchymal transition process, may represent alternative sources of myofibroblasts when local fibroblasts are not able to satisfy the requirement for these cells during repair. These diverse cell types probably contribute to the appearance of myofibroblast subpopulations which show specific biological properties and which are important to understand in order to develop new therapeutic strategies for treatment of fibrotic and scarring diseases.

Figure 1

Schematic illustration showing the evolution of the (myo)fibroblast phenotype. The myofibroblastic modulation of fibroblastic cells begins with the appearance of the proto-myofibroblast, whose stress fibers contain only β- and γ-cytoplasmic actins and evolves, but not necessarily always, into the appearance of the differentiated myofibroblast, the most common variant of this cell, with stress fibers containing α-smooth muscle actin. The myofibroblast may disappear by apoptosis; the deactivation leading to a quiescent phenotype has not been clearly demonstrated at least in vivo. TGF-β1: transforming growth factor-β1; ECM: extracellular matrix. Modified from [38].

Figure 2

Myofibroblast origins. The main myofibroblast progenitor after injury of different tissues appears to be locally residing fibroblasts. Indeed, various cell types can acquire a myofibroblastic phenotype; these diverse origins lead to distinct myofibroblast sub-populations. EMT: epithelial- and endothelial-to-mesenchymal transition.