Abstract
Several recent studies have demonstrated that endothelial to mesenchymal transition (EndoMT), a newly recognized type of cellular transdifferentiation may be an important source of myofibroblasts during the development of experimentally induced pulmonary, cardiac and kidney fibrosis. EndoMT is a complex biological process induced by members of the transforming growth factor (TGF-β) family of regulatory polypeptides in which endothelial cells adopt a mesenchymal or myofibroblastic phenotype acquiring motile and contractile properties and initiating expression of mesenchymal cell products such as α smooth muscle actin (α-SMA) and type I collagen. Although these experimental studies provide compelling evidence for the participation of EndoMT in the development of experimentally-induced fibrotic processes the precise role of EndoMT in the pathogenesis of human fibrotic disorders requires confirmation and validation from studies of human clinical pathologic conditions. Such confirmation should lead to a change in the paradigm of the origin of profibrogenic myofibroblasts involved in human fibrotic diseases. Further understanding of the molecular mechanisms and the regulatory pathways involved in EndoMT may lead to the development of novel therapeutic approaches for the incurable and often devastating fibrotic disorders.
Highlights
It is generally accepted that activated mesenchymal cells or myofibroblasts play a crucial role in the pathogenesis of various fibrotic diseases including interstitial pulmonary fibrosis, systemic sclerosis and liver or cardiac fibrosis being responsible for the exaggerated production and accumulation of extracellular matrix proteins in various organs affected by these diseases [1,2,3,4]
Myofibroblasts in the fibrotic diseases are derived from at least three sources: 1) expansion and activation of resident tissue fibroblasts [7,8]; 2) transition of epithelial cells into mesenchymal cells, a process known as epithelial-mesenchymal transition [9,10,11,12,13,14]; and 3) tissue migration of bone marrow-derived circulating fibrocytes [15,16]
Endothelial to mesenchymal transition (EndoMT), a newly recognized type of cellular transdifferentiation [17], has emerged as another possible source of tissue myofibroblasts which may play a crucial role in the pathogenesis of fibrotic diseases [18,19]
Summary
It is generally accepted that activated mesenchymal cells or myofibroblasts play a crucial role in the pathogenesis of various fibrotic diseases including interstitial pulmonary fibrosis, systemic sclerosis and liver or cardiac fibrosis being responsible for the exaggerated production and accumulation of extracellular matrix proteins in various organs affected by these diseases [1,2,3,4]. An extensive study by Zeisberg et al [24] examined the role of EndoMT in three murine models of chronic kidney disease: unilateral ureteral obstructive nephropathy, streptozotocin-induced diabetic nephropathy and a model of Alport renal disease The results of these studies indicated that 30-50% of myofibroblasts in the fibrotic kidneys, identified by their expression of a fibroblast phenotype and a-SMA, display the endothelial cell specific CD31 surface marker indicating their endothelial cell origin. Confocal microscopy demonstrated the expression of endothelial cell markers (CD-31 and CD-34) in mesenchymal cells embedded within the subendothelial neointima of small pulmonary arteries in lung specimens from patients with Systemic Sclerosis These two studies provide strong support to the concept that EndoMT may play an important role in the pathogenesis of human fibrotic diseases. The firm demonstration of the occurrence of EndoMT in human fibrotic diseases and further understanding of the molecular mechanisms involved may lead to the pharmacologic modulation or abrogation of this pathway in human fibrotic disorders and may represent a novel therapeutic approach for these devastating diseases
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