TGF-β-Induced Endothelial-Mesenchymal Transition in Fibrotic Diseases - PubMed (original) (raw)

Review

TGF-β-Induced Endothelial-Mesenchymal Transition in Fibrotic Diseases

Evangelia Pardali et al. Int J Mol Sci. 2017.

Abstract

Fibrotic diseases are characterized by net accumulation of extracellular matrix proteins in affected organs leading to their dysfunction and ultimate failure. Myofibroblasts have been identified as the cells responsible for the progression of the fibrotic process, and they originate from several sources, including quiescent tissue fibroblasts, circulating CD34⁺ fibrocytes and the phenotypic conversion of various cell types into activated myofibroblasts. Several studies have demonstrated that endothelial cells can transdifferentiate into mesenchymal cells through a process termed endothelial- mesenchymal transition (EndMT) and that this can give rise to activated myofibroblasts involved in the development of fibrotic diseases. Transforming growth factor β (TGF-β) has a central role in fibrogenesis by modulating the fibroblast phenotype and function, inducing myofibroblast transdifferentiation and promoting matrix accumulation. In addition, TGF-β by inducing EndMT may further contribute to the development of fibrosis. Despite extensive investigation of the pathogenesis of fibrotic diseases, no effective treatment strategies are available. Delineation of the mechanisms responsible for initiation and progression of fibrotic diseases is crucial for the development of therapeutic strategies for the treatment of the disease. In this review, we summarize the role of the TGF-β signaling pathway and EndMT in the development of fibrotic diseases and discuss their therapeutic potential.

Keywords: Smad; TGF-β signaling; endothelial cells; endothelial-mesenchymal transition; extracellular matrix; fibrosis; myofibroblasts.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1

Figure 1

Origin of the myofibroblasts in fibrotic diseases. Resident fibroblasts, circulating progenitors, pericytes, epithelial cells undergoing epithelial to mesenchymal transition (EMT) and endothelial cells undergoing endothelial-mesenchymal transdifferentiation (EndMT) are documented sources of myofibroblasts in fibrotic diseases. ECM, extracellular matrix; FSP, fibroblast specific protein; TGF-β, transforming growth factor-β; α-SMA, α-smooth muscle actin.

Figure 2

Figure 2

(A) Transforming growth factor-β (TGF-β) signaling. TGF-β binds the TGF-β type II receptor (TβRII), which recruits and activates the type I TGF-β receptor ALK5. ALK5 in turn phosphorylates Smad2/3, which form a complex with Smad4. In addition, TGF-β activates non-Smad pathways. TGF-β Smad and non-Smad pathways regulate the transcription of TGF-β target genes expressed in myofibroblasts, such as α-smooth muscle actin (SMA), fibronectin and collagen, as well as the transcription regulators Snail involved in EndMT; (B) Schematic representation of the molecular mechanisms involved in EndMT. The TGF-β, Notch, Wnt, sonic hedgehog (SHh), caveolin (CAV)-1, endothelin (ET)-1 and hypoxia pathways induce EndMT, which leads to decreased expression of endothelial markers vascular endothelial (VE)-cadherin and CD31 and a gain of mesenchymal markers such as α-SMA, fibroblast specific protein (FSP)-1, vimentin and fibronectin. EndMT results in the transdifferentiation of ECs into mesenchymal cells, which subsequently differentiate into myofibroblasts, thereby contributing to the development of fibrotic diseases. ERK, extracellular signal-regulated kinase; JNK, jun N-terminal kinase; MMP, matrix metalloproteinase; PKC, protein kinase C; TIMPs, tissue inhibitors of metalloproteinases.

References

    1. Tomasek J.J., Gabbiani G., Hinz B., Chaponnier C., Brown R.A. Myofibroblasts and mechano-regulation of connective tissue remodelling. Nat. Rev. Mol. Cell Biol. 2002;3:349–363. doi: 10.1038/nrm809. - DOI - PubMed
    1. Wynn T.A., Ramalingam T.R. Mechanisms of fibrosis: Therapeutic translation for fibrotic disease. Nat. Med. 2012;18:1028–1040. doi: 10.1038/nm.2807. - DOI - PMC - PubMed
    1. Karsdal M.A., Manon-Jensen T., Genovese F., Kristensen J.H., Nielsen M.J., Sand J.M., Hansen N.U., Bay-Jensen A.C., Bager C.L., Krag A., et al. Novel insights into the function and dynamics of extracellular matrix in liver fibrosis. Am. J. Physiol. Gastrointest. Liv. Physiol. 2015;308:G807–G830. doi: 10.1152/ajpgi.00447.2014. - DOI - PMC - PubMed
    1. Rockey D.C., Bell P.D., Hill J.A. Fibrosis—A common pathway to organ injury and failure. N. Engl. J. Med. 2015;372:1138–1149. doi: 10.1056/NEJMra1300575. - DOI - PubMed
    1. Wynn T.A. Common and unique mechanisms regulate fibrosis in various fibroproliferative diseases. J. Clin. Investig. 2007;117:524–529. doi: 10.1172/JCI31487. - DOI - PMC - PubMed

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