The myofibroblast: phenotypic characterization as a prerequisite to understanding its functions in translational medicine

Abstract

The phrase translational research' conveys the idea of the pursuit of applications for the treatment of human disease. The myofibroblast, long known for having a role in wound-healing, and for its presence in fibrotic conditions and tumour stroma, is becoming a focus for translational research, not least through its increasingly documented role as a tumour-promoting cell. In fibroproliferative conditions, cancer and tissue engineering, the myofibroblast, derived partly and possibly from circulating bone-marrow-derived cells and epithelial-to-mesenchymal transformation, is attracting great attention. In cancer, this cell was initially regarded as a barrier to tumour dissemination, but there is now a growing body of evidence to indicate that it is an active participant in tumour progression. While the involvement of the myofibroblast in these pathological processes is pushing the myofibroblast into the limelight of translational medicine as a target for potential anti-fibrotic and anti-cancer therapy, there are still numerous indications from the literature that the myofibroblast is a poorly understood cell in terms of its differentiation.Partly, this is due to a failure to appreciate the contribution of electron microscopy to understanding the nature of this cell. This paper, therefore, is devoted to detailing the principal phenotypic characteristics of the myofibroblast and promotes the argument that understanding how the myofibroblast carries out its roles in normal biological and in pathological processes will be enhanced by a sound understanding of its cellular differentiation, which in turn arguably demands a significant ultrastructural input.

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(A): Tumour stroma myofibroblast from squamous cell carcinoma. It shows abundant rER cisternae in an ordered array, peripheral myofilaments (m) and a colinear extracellular fibronectin fibril at the fibronexus (FNX).Note how the fibronectin fibril is dense and straight, and projects away from the cell surface into matrix.The asterisked arrow indicates a focal area of fibronectin adjacent to the cell surface and mimicking lamina. Reproduced with permission from BC Decker Inc (Hamilton, Canada) from Fig. 2 in Journal of Otolaryngology. 1996; 25: 361–2. (B): ‘External’ lamina (arrow) around a perineur-ial cell from a normal cutaneous nerve, showing a paler staining quality and faithful adherence to the cell surface contour.

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Diagrammatic representation of the myofibroblast, in comparison with the fibroblast and the smooth-muscle cell. Abbreviations: AP, attachment plaque; c, collagen secretion granule; FD, focal density; FF, fibronectin fibril; FNX, fibronexus; G, Golgi apparatus; L, lamina; M, myofilament bundle; N, nucleus; RER, rough endoplasmic reticulum; SC, surface (plasmalemmal) caveolae; SPL, subplasmalemmal linear density (focal adhesion).Drawing by Paul Chantry.

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Diagrammatic representation of the fibronexus (FNX), showing the connection through the membrane at a plaque (p) of myofilaments (mf) and fibronectin filaments (ff).fd, focal density; pm, plasmalemma.Drawing by Paul Chantry. Reproduced with permission from Histology Histopathology. 2001; 16: 57–70.

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Light microscopy features of reactive myofibroblasts from the stroma of squamous cell carcinoma.

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(A): Peripherally located bundles of actin filaments in epithe-lium of renal tubulointerstitial fibrosis.(B): Stromal cell showing some rough endoplasmic reticulum and a slender bundle of actin filaments, but no fibronexuses. Reproduced with permission from Journal of Submicroscopic Cytology and Pathology. 2003; 35: 221–33.