Role of Endothelial-Mesenchymal Transition (EndoMT) in the Pathogenesis of Fibrotic Disorders

The accumulation of a large number of myofibroblasts is responsible for exaggerated and uncontrolled production of extracellular matrix during the development and progression of pathological fibrosis. Myofibroblasts in fibrotic tissues are derived from at least three sources: expansion and activation of resident tissue fibroblasts, transition of epithelial cells into mesenchymal cells (epithelial-mesenchymal transition, EMT), and tissue migration of bone marrow–derived circulating fibrocytes. Recently, endothelial to mesenchymal transition (EndoMT), a newly recognized type of cellular transdifferentiation, has emerged as another possible source of tissue myofibroblasts. EndoMT is a complex biological process in which endothelial cells lose their specific markers and acquire a mesenchymal or myofibroblastic phenotype and express mesenchymal cell products such as α smooth muscle actin (α-SMA) and type I collagen. Similar to EMT, EndoMT can be induced by transforming growth factor (TGF-β). Recent studies using cell-lineage analysis have demonstrated that EndoMT may be an important mechanism in the pathogenesis of pulmonary, cardiac, and kidney fibrosis, and may represent a novel therapeutic target for fibrotic disorders.The fibrotic diseases encompass a wide spectrum of clinical entities including multisystemic diseases such as systemic sclerosis,^1,2 multifocal fibrosclerosis,^3,4 sclerodermatous graft versus host disease in bone marrow transplant recipients,⁵ and the recently recognized nephrogenic systemic fibrosis,^6,7 as well as organ-specific disorders such as pulmonary, liver, and kidney fibrosis.^8–10 Although their etiology and causative mechanisms are vastly different, they share the common feature of disordered and exaggerated deposition of extracellular matrix in affected tissues. Elevated expression of genes encoding matrix proteins is a common and characteristic feature of these conditions, and the resulting fibrosis disrupts the normal architecture of the affected organs, ultimately leading to their dysfunction and failure.^11–13 Indeed, it is the persistent activation of fibroblastic cells regarding the production of extracellular matrix macromolecules that distinguishes controlled repair such as that occurring during normal wound healing from the uncontrolled fibrosis that is the hallmark of fibrotic diseases. Because fibrotic diseases affect a wide spectrum of organs and a large number of individuals, their devastating effects cause an enormous burden on health resources, with severe economic consequences. The usually progressive nature of these diseases and the current absence of effective treatment compound the seriousness of the problem.Although the etiology of the fibrotic disorders is quite diverse, and their pathogenesis is variable and dependent on the causative agent or initiating event, a common feature is the presence in affected tissues of large numbers of activated fibroblasts or myofibroblasts. These cells play a prominent role in the fibrotic process and display unique biological functions, including increased production of fibrillar type I and type III collagens, initiation of expression of α-smooth muscle actin (α-SMA), a molecular marker of activated myofibroblasts, and reduction in the expression of genes encoding extracellular matrix–degradative enzymes.^14–17 Regardless of the etiological event, the accumulation of activated fibroblasts (myofibroblasts) in affected tissues and the persistence of their elevated biosynthetic functions are crucial determinants of the extent and rate of progression of the fibrotic diseases, and of their clinical course, response to therapy, prognosis, and mortality.The origins of the mesenchymal cells responsible for the exaggerated and uncontrolled production of collagen and other extracellular matrix proteins in the fibrotic disorders have not been completely elucidated. Extensive research studies have shown that these cells originate from several sources, including expansion of resident tissue fibroblasts, migration and tissue accumulation of bone marrow–derived circulating fibrocytes, or from epithelial cells that have undergone epithelial to mesenchymal transition (EMT). More recent studies, however, have demonstrated that endothelial cells are also capable of undergoing endothelial to mesenchymal transition (EndoMT) and that this transition might be an important source of the mesenchymal cells participating in the fibrotic process. Here, the experimental evidence supporting the role of EndoMT in the pathogenesis of fibrotic disorders will be reviewed.