Heterogeneity of myofibroblast phenotypic features: an example of fibroblastic cell plasticity

Abstract

Granulation tissue fibroblasts (myofibroblasts) develop several ultrastructural and biochemical features of smooth muscle (SM) cells, including the presence of microfilament bundles and the expression of alpha-SM actin, the actin isoform present in SM cells and myoepithelial cells and particularly abundant in vascular SM cells. Myofibroblasts have been suggested to play a role in wound contraction and in retractile phenomena observed during fibrotic diseases. When contraction stops and the wound is fully epithelialized, myofibroblasts containing alpha-SM actin disappear, probably as a result of apoptosis, and the scar classically becomes less cellular and composed of typical fibroblasts with well-developed rough endoplasmic reticulum but with no more microfilaments. In contrast, alpha-SM actin expressing myofibroblasts persist in hypertrophic scars and in fibrotic lesions of many organs, including stroma reaction to epithelial tumours, where they are allegedly involved in retractile phenomena as well as in extracellular matrix accumulation. The mechanisms leading to the development of myofibroblastic features remain to be investigated. In vivo and in vitro investigations have shown that gamma-interferon exerts an antifibrotic activity at least in part by decreasing alpha-SM actin expression whereas heparin increases the proportion of alpha-SM actin positive cells. Recently, we have observed that the subcutaneous administration of transforming growth factor-beta 1 to rats results in the formation of a granulation tissue in which alpha-SM actin expressing myofibroblasts are particularly abundant. Other cytokines and growth factors, such as platelet-derived growth factor, basic fibroblast growth factor and tumour necrosis factor-alpha, despite their profibrotic activity, do not induce alpha-SM actin in myofibroblasts. In conclusion, fibroblastic cells are relatively undifferentiated and can assume a particular phenotype according to the physiological needs and/or the microenvironmental stimuli. Further studies on fibroblast adaptation phenomena appear to be useful for the understanding of the mechanisms of development and regression of pathological processes such as wound healing and fibrocontractive diseases.

Tenocyte responses to mechanical loading in vivo: A role for local insulin‐like growth factor 1 signaling in early tendinosis in rats

“…Transforming growth factor ␤1, platelet-derived growth factor receptor ␤, and IGF-1 are all reported to be up-regulated in tendinosis biopsy samples, even in the chronic stage (months after loading has been discontinued) (36)(37)(38). Although the current study suggests that the stimulus for tenocyte proliferation may be driven locally by load-induced proliferation, in chronic stages other factors, such as hypoxia or transformation to a fibrotic phenotype, may play a role in persistent growth factor up-regulation and proliferation (21,(39)(40)(41).…”

Connective Tissue Metabolism and Gingival Overgrowth

“…Mechanical forces contribute in some way to fibroblast selection and differentiation (Kessler et al, 2001;Schild and Trueb, 2002). As discussed above, deregulated cytokine expression and unique aspects of gingival fibroblast metabolism are all likely to be important contributing factors in gingival overgrowth and development of highly synthetic or proliferative fibroblast phenotypes (Schmitt-Graff et al, 1994;Vaughan et al, 2000). In addition, a reduced rate of apoptosis is reported to contribute to the accumulation of gingival fibroblasts (Fujimori et al, 2001), perhaps with a greater synthetic or proliferative phenotype in nifedipine-induced gingival overgrowth (Kessler et al, 2001;Schild and Trueb, 2002), though this is a novel and understudied area at this time.…”

Fibroblasts from Human Spleen Regulate NK Cell Differentiation from Blood CD34+ Progenitors Via Cell Surface IL-15

“…The medium was changed every 3-4 days until a substantial outgrowth of cells was observed, at which point cells were trypsinized (Life Technologies) and subsequently subcultured at a 1:2 split ratio for up to three passages before analysis. The fibroblastic nature of the cultures was assessed by their homogeneous staining for anti-smooth muscle-actin with a typical stress fiber distribution characteristic of myofibroblasts (8). All cells also showed strong staining for other mesenchymal Ags, including vimentin, fibronectin, and collagen type I and III.…”