Myofibroblasts: Function, Formation, and Scope of Molecular Therapies for Skin Fibrosis

Abstract

Myofibroblasts are contractile, α-smooth muscle actin-positive cells with multiple roles in pathophysiological processes. Myofibroblasts mediate wound contractions, but their persistent presence in tissues is central to driving fibrosis, making them attractive cell targets for the development of therapeutic treatments. However, due to shared cellular markers with several other phenotypes, the specific targeting of myofibroblasts has long presented a scientific and clinical challenge. In recent years, myofibroblasts have drawn much attention among scientific research communities from multiple disciplines and specialisations. As further research uncovers the characterisations of myofibroblast formation, function, and regulation, the realisation of novel interventional routes for myofibroblasts within pathologies has emerged. The research community is approaching the means to finally target these cells, to prevent fibrosis, accelerate scarless wound healing, and attenuate associated disease-processes in clinical settings. This comprehensive review article describes the myofibroblast cell phenotype, their origins, and their diverse physiological and pathological functionality. Special attention has been given to mechanisms and molecular pathways governing myofibroblast differentiation, and updates in molecular interventions.

Fibroblast Differentiation and Matrix Remodeling Impaired under Simulated Microgravity in 3D Cell Culture Model

“…To elucidate the effect of microgravity on fibroblast differentiation, we first studied αSMA gene expression, a prominent marker of myofibroblasts [ 15 , 38 ], using real-time quantitative polymerase chain reaction (RT-qPCR) ( Figure 2 A). As expected, we found significantly higher αSMA expression upon TGF-β1 stimulation for both 1 g and sμG conditions, but a significant reduction in αSMA expression was observed under sμG conditions when compared to 1 g conditions, whether sμG samples were TGF-β1 stimulated or not.…”

“…Upon TGF-β1 binding to its receptors, Smad2/3 is phosphorylated, binds to Smad4 and the complex is translocated from the cytoplasm into the nucleus [ 15 ]. A positive correlation of αSMA expression and nuclear translocation of Smad2/3 has been reported in human dermal fibroblasts [ 17 , 40 ].…”

“…TGF-β1 is secreted by a multitude of cells when a tissue is injured. Upon TGF-β1 activation, the TGF-β1 pathway causes Smad2/3 proteins to translocate to the nucleus and initiate the myofibroblast differentiation program [ 15 , 16 , 17 ]. Myofibroblasts are characterized by high expression of alpha smooth muscle actin (αSMA), which allows them to gain their contractile properties, thereby possessing the ability to physically remodel the ECM [ 18 , 19 ].…”

“…Myofibroblasts are characterized by high expression of alpha smooth muscle actin (αSMA), which allows them to gain their contractile properties, thereby possessing the ability to physically remodel the ECM [ 18 , 19 ]. In addition, myofibroblasts are known to secrete a variety of extracellular matrix components, e.g., collagen, fibronectin, hyaluronic acid, as well as metalloproteinases, all facilitating the tissue remodeling process [ 15 , 20 , 21 ].…”

Molecular Mechanisms and Cellular Contribution from Lung Fibrosis to Lung Cancer Development

“…The resulting crosslinks increase the strength of these collagen networks and prevent enzymatic degradation, thereby strengthening the injured tissue [186][187][188][189]. Myofibroblasts can originate in several ways, including from differentiation from fibroblasts, a key process in normal wound healing, orchestrated by growth factors such as TGF-β, WNT, fibronectin cloths, and tissue stiffness [190]. The principal growth factor for myofibroblasts formation is TGF-β, which directly induces extracellular matrix production and αSMA expression.…”