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.

Highlights

  • Key Laboratory of Bioactive Materials for the Ministry of Education, College of Life Sciences, Welsh Kidney Research Unit, Division of Infection and Immunity, Cardiff Institute of Tissue Engineering and Repair (CITER), School of Medicine, Cardiff University, Heath Park, Cardiff CF14 4XN, UK; Regenerative Biology Group, Oral and Biomedical Sciences, Cardiff Institute of Tissue Engineering and Repair (CITER), School of Dentistry, Cardiff University, Heath Park, Cardiff CF14 4XY, UK

  • TGF-β1 is locked within the extracellular matrix (ECM) by latency-associated peptide (LAP) and latent TGF-β1-binding protein (LTBP), and is released by proteolysis or integrin-dependent mechanotransducdiminished expression in myofibroblasts

  • Wnt signalling stimulated by TGF-β1-induced inhibition of Dickkopf-related protein-1 (DKK1) was shown to induce myofibroblast differentiation, up-regulate the release of ECM components and induce fibrosis [82,83,84]

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Summary

Myofibroblasts

Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. The incorporation of α-SMA into actin stress fibres grants the myofibroblast contractile power, approximately 2-fold that of the force of fibroblasts, when cultured on substrates with high elastomer stiffness [8,9,10]. Biomolecules 2021, 11, 1095 fibronectin (FN), and extra domain A fibronectin (EDA–FN) distinguish the hallmarks of myofibroblasts [11]. This elevated ECM content is not always causally linked, driving the myofibroblast differentiation process. Studies describing an array of functions and regulatory factors exhibited by myofibroblasts have suggested roles beyond wound contraction and scar formation, including macrophage-like phagocytosis [17], immunomodulation [18,19], and autophagy [20]. We summarise recent advancements towards targeting these cells with therapeutic molecular interventions

Myofibroblast Origins
Myofibroblasts in Skin Fibrosis
The Canonical Pathway
Mechanotransduction
Interventional Strategies to Target Myofibroblasts for Scarless Skin Healing
Experimental and Pre-Clinical Interventions for Myofibroblast Differentiation
Immunomodulating Biomolecules for Fibrosis Attenuation
Targeted Myofibroblast Apoptosis
Antioxidant Therapeutics
Future Perspectives for the Discovery of Novel Therapeutics
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