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.
Highlights
Fibrotic diseases affect a large number of individuals resulting in high morbidity and mortality due to the lack of effective therapies [1]
The etiology of fibrotic diseases is different, fibrosis is defined by the accumulation of fibrous connective tissue and an excess of extracellular matrix (ECM) components, such as collagen and fibronectin in and around inflamed or damaged tissue, which eventually lead to organ malfunction and death [3,4,5]
Smad3 expression was shown to be downregulated in a model of bleomycin (BLM)-induced pulmonary fibrosis [100] and in ureteral obstruction-induced kidney fibrosis [101], resulting in increased expression of a-SMA. These results suggest that Transforming growth factor β (TGF-β)/Smad3 signaling regulates the expression of Smad3 itself, resulting in a negative feedback loop, which may play important role in the pathogenesis of fibrotic diseases
Summary
Fibrotic diseases affect a large number of individuals resulting in high morbidity and mortality due to the lack of effective therapies [1]. TGF-β contributes to the development of fibrotic diseases by regulating fibroblast phenotype and function by inducing cell differentiation into myofibroblasts [29]. Apart from its function regulating developmental vascular homeostasis, it is clear that EndMT can participate in various adult pathologic settings, including cancer, myocardial infarction [24], cerebral cavernous malformations [56], pulmonary hypertension and different types of organ fibrosis [57]. In this sense, EndMT has emerged as another possible source of tissue myofibroblasts [57]. Shear stress was shown to activate TGF-β signaling in ECs, resulting in increased expression of α-SMA and induction of EndMT [82,83]
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