Review
Endothelial–mesenchymal transition and its contribution to the emergence of stem cell phenotype

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Abstract

Vascular endothelial cells can demonstrate considerable plasticity to generate other cell types during embryonic development and disease progression. This process occurs through a cell differentiation mechanism known as endothelial–mesenchymal transition (EndMT). The generation of mesenchymal cells from endothelium is a crucial step in endothelial cell differentiation to several lineages including fibroblasts, myofibroblasts, mural cells, osteoblasts, chondrocytes, and adipocytes. Such differentiation patterns have been observed in systems of cardiac development, fibrosis, diabetic nephropathy, heterotopic ossification and cancer. Here we describe the EndMT program and discuss the current evidence of EndMT-mediated acquisition of stem cell characteristics and multipotent differentiation capabilities.

Section snippets

The molecular and cellular basis of EndMT

Endothelial cells compose the inner lining of blood vessels and lymphatic vessels [7]. These cells, which are anatomically similar to squamous epithelium, demonstrate apical-basal polarity and are tightly bound by adherens junctions and tight junctions. These cells express a distinct set of biomarkers that allow investigators to distinguish them from other cell types including VE-cadherin, CD31, TIE1, TIE2, von Willebrand factor (vWF), and cytokeratins. During EndMT, expression of these markers

EndMT in embryonic development

EndMT was initially discovered as an essential mechanism of heart development [47]. Vascular endothelial cells in the atriventricular canal and the outflow tract undergo EndMT and invade surrounding tissues to form the valves and septa of the heart [21]. Several mechanistic studies have shown the crucial importance of TGF-β/BMP ligands and receptors in embryonic EndMT. Targeted inhibition of TGF-β2, BMP2, BMP4, ALK2, ALK5, endoglin, or β-glycan in mice shows defective heart development due to a

EndMT in fibrosis

Although EndMT is an embryonic mechanism that is normally dormant in the adult organism, pathological conditions can arise that awaken this phenomenon. One such condition that affects most organs as a result of injury, inflammation or aging is fibrosis [2], [48]. EMT is known to be essential for the formation of fibrotic tissues [2], but more recent evidence suggests that EndMT also contributes to fibrosis [7], [22] (Fig. 3).

Cardiac fibrosis is a common result of heart failure. Myocardial

EndMT in cancer

The tumor microenvironment plays an important role in cancer growth, angiogenesis and metastasis [55]. One component of this microenvironment that regulates these processes is cancer-associated fibroblasts (CAFs), which are part of the tumor stroma. In an elegant study, Zeisberg et al. [56] showed that up to 40% of CAFs were formed by EndMT in two distinct mouse models of cancer. CAFs in these models co-expressed the endothelial marker CD31 along with mesenchymal markers FSP-1 or α-SMA.

EndMT and the stem cell phenotype

In a recent study of a rare bone disease called fibrodysplasia ossificans progressiva (FOP), vascular endothelial cells were shown to differentiate into chondrocytes and osteoblasts through EndMT [17], [62]. In patients with FOP, acute inflammation triggers heterotopic ossification in soft tissues [63], [64]. FOP patients carry a heterozygous germ-line mutation (R206H) in the TGF-β/BMP receptor ALK2 [65]. Studies have shown that R206H is a gain of function mutation that causes the receptor to

Competing interests

None.

Acknowledgements

This work was supported by grants R01HL112860 (to D. Medici), CA125550, CA155370, CA151925, DK55001, and DK81576 (to R. Kalluri) from the National Institutes of Health, and a grant from the John Butler Mulliken Foundation (to D. Medici) R. Kalluri is a Champalimaud Investigator.

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