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.

In search of definitions: Cancer‐associated fibroblasts and their markers

“…This αSMA-induced mechanical stress plays a considerable role in the contraction and maturation of the granulation tissue-new connective tissue that forms on the wound surface during the injury healing process. 27 As the number of myofibroblasts is much higher in the tumor microenvironment, αSMA has become one of the go-to markers for identifying CAF populations. 28,29 In addition to its role as a marker for cancer-associated fibroblasts, αSMA has also been identified as a prominent prognostic factor in tumor patients.…”

Origin and functional heterogeneity of fibroblasts

“…B, Proposed evolution of PFs, MSCs, and RQFs in development and aging, and matching cellular plasticity (fibroblast activation protein), FSP1/S100A4 (fibroblast-specific protein 1), THY1/CD90 (Thy1.1 and Thy1.2 in mice), and αSMA (alpha-smooth muscle actin, encoded by ACTA2); these are seen in CAFs as well.4,5 αSMA is typically associated with a distinct subtype of fibroblast referred to as myofibroblasts (Table 1).4,6,40 The reorganization of the actin skeleton in myofibroblasts together with αSMA expression may enhance their contractile properties in wound healing. 40 Since αSMA+ myofibroblasts are usually absent in normal interstitial spaces (with the exception of smooth muscles cells in perivascular niches), but increase in number in fibrotic or cancerous lesions, they are often thought of as pathology-associated fibroblasts.…”

Skin regeneration of amphibians: A novel model for skin regeneration as adults

“…In rodents (mice and rats), genetic tools for lineage tracing are available. With this advantage, it has recently been shown that there are multiple fibroblast subpopulations with distinct functions and that myofibroblasts have multiple origins in wound healing (reviewed by Driskell & Watt, 2015;Micallef et al, 2012). The formation of fibrous scar tissue, fibrosis, which is mediated by myofibroblasts, is not restricted to injured skin but is widely observed in other tissues after chronic damage.…”