Myofibroblasts

Abstract

Purpose of review Interest in the myofibroblast as a key player in propagation of chronic progressive fibrosis continues to elicit many publications, with focus on its cellular origins and the mechanisms underpinning their differentiation and/or transition. The objective of the review is to highlight this recent progress. Recent findings The epithelial origin of the myofibroblast in fibrosis has been challenged by recent studies, with the pericyte suggested as a possible precursor instead. Additional signaling pathways, including Notch, Wnt, and hedgehog, are implicated in myofibroblast differentiation. The importance of NADPH oxidase 4 was highlighted recently to suggest a potential link between cellular/oxidative stress and the genesis of the myofibroblast. Recent observations on the importance of lysophosphatidic acid in fibrosis suggest that this may be due, in part, to its ability to regulate myofibroblast differentiation. Finally, there is increasing evidence for the role of epigenetic mechanisms in regulating myofibroblast differentiation, including DNA methylation and miRNA regulation of gene expression. Summary These recent discoveries open up a whole new array of potential targets for novel antifibrotic therapies. This is of special importance given the current bleak outlook for chronic progressive fibrotic diseases, such as scleroderma, due to lack of effective therapies.

Targeting the Myofibroblast Genetic Switch: Inhibitors of Myocardin-Related Transcription Factor/Serum Response Factor–Regulated Gene Transcription Prevent Fibrosis in a Murine Model of Skin Injury

“…The expression of a-smooth muscle actin (a-SMA) is a widely recognized marker for this transition but it also contributes to the maintenance of fibrosis (Sappino et al, 1990;Boukhalfa et al, 1996;Zhang et al, 1996;Tomasek et al, 2002;Gilbane et al, 2013;Hu and Phan, 2013). There are multiple signaling pathways that induce myofibroblast transition.…”

“…A central feature of virtually all diseases of fibrosis is the activation of fibroblasts and their transition into myofibroblasts (Sappino et al, 1990;Boukhalfa et al, 1996;Zhang et al, 1996;Beyer et al, 2010;Hinz et al, 2012;Wynn and Ramalingam, 2012;Gilbane et al, 2013;Hu and Phan, 2013). The expression of a-smooth muscle actin (a-SMA) is a widely recognized marker for this transition but it also contributes to the maintenance of fibrosis (Sappino et al, 1990;Boukhalfa et al, 1996;Zhang et al, 1996;Tomasek et al, 2002;Gilbane et al, 2013;Hu and Phan, 2013).…”

FIZZ1-Induced Myofibroblast Transdifferentiation from Adipocytes and Its Potential Role in Dermal Fibrosis and Lipoatrophy

“…Therefore, FIZZ1 could cause dedifferentiation of adipocytes followed by differentiation into myofibroblasts in vitro, consistent with a role in adipocyte transdifferentiation to the myofibroblast, a key cell in pathogenesis of chronic fibrosis. 4,29 However, because FIZZ1 caused incomplete (<60%) inhibition of adipocyte gene marker expression, direct adipocyte-to-myofibroblast transdifferentiation without going through a dedifferentiated state cannot be ruled out.…”

“…3 Moreover, suppression of adipogenesis results in marked reduction in myofibroblast numbers in the wound bed, suggesting that adipocytes may also be important in chronic fibrotic disorders wherein myofibroblasts are known to play a key role. 4 However, other studies suggest that inhibition of adipocyte differentiation by profibrotic factors such as transforming growth factor (TGF)-b1 is associated with dermal fibrosis in an animal model. 5 The mechanism may be mediated by TGF-b1 suppression of peroxisome proliferator-activated receptor (PPAR)-g expression a key indicator of adipocyte differentiation.…”

Epithelial and endothelial mesenchymal transition and their role in diabetic kidney disease

“…During EndoMT, endothelial cells (EC) lose their molecular markers such as VE-cadherin, detach from endothelial layer and begin the expression of mesenchymal cell products (e.g. α-SMA) (20).…”