ReviewEndothelial–mesenchymal transition and its contribution to the emergence of stem cell phenotype
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.
References (72)
Epithelial–mesenchymal transitions in development and pathologies
Current Opinion in Cell Biology
(2003)- et al.
TGF-beta signaling in cancer—a double-edged sword
Trends in Cell Biology
(2001) - et al.
Slug is an essential target of TGFbeta2 signaling in the developing chicken heart
Developmental Biology
(2000) - et al.
TGFbeta2 and TGFbeta3 have separate and sequential activities during epithelial–mesenchymal cell transformation in the embryonic heart
Developmental Biology
(1999) - et al.
Temporal and distinct TGFbeta ligand requirements during mouse and avian endocardial cushion morphogenesis
Developmental Biology
(2002) - et al.
Signaling via the Tgf-β type I receptor Alk5 in heart development
Developmental Biology
(2008) - et al.
Atrioventricular cushion transformation is mediated by ALK2 in the developing mouse heart
Developmental Biology
(2005) - et al.
Twist, a master regulator of morphogenesis, plays an essential role in tumor metastasis
Cell
(2004) - et al.
FGF-2-mediated signal transduction during endothelial mesenchymal transformation in corneal endothelial cells
Experimental Eye Research
(2006) - et al.
Notch initiates the endothelial-to-mesenchymal transition in the atrioventricular canal through autocrine activation of soluble guanylyl cyclase
Developmental Cell
(2011)
Type I collagen promotes epithelial–mesenchymal transition through ILK-dependent activation of NF-kappaB and LEF-1
Matrix Biology
Discoidin domain receptor 2 is a critical regulator of epithelial–mesenchymal transition
Matrix Biology
Structural analysis of endocardial cytodifferentiation
Developmental Biology
Mechanistic connection between inflammation and fibrosis
Kidney International. Supplement
Endothelial–mesenchymal transition as a novel mechanism for generating myofibroblasts during diabetic nephropathy
American Journal of Pathology
Endothelial–myofibroblast transition contributes to the early development of diabetic renal interstitial fibrosis in streptozotocin-induced diabetic mice
American Journal of Pathology
Insights from a rare genetic disorder of extra-skeletal bone formation, fibrodysplasia ossificans progressiva (FOP)
Bone
Calcification of multipotent prostate tumor endothelium
Cancer Cell
The epithelial–mesenchymal transition generates cells with properties of stem cells
Cell
The basics of epithelial–mesenchymal transition
Journal of Clinical Investigation
The mesenchymal cell, its role in the embryo, and the remarkable signaling mechanisms that create it
Developmental Dynamics
Epithelial–mesenchymal transitions: the importance of changing cell state in development and disease
Journal of Clinical Investigation
Cellular and molecular mechanisms of fibrosis
Journal of Pathology
Epithelial–mesenchymal transition and its implications for fibrosis
Journal of Clinical Investigation
The role of endothelial-to-mesenchymal transition in cancer progression
British Journal of Cancer
Regulation of endothelial cell plasticity by TGF-β
Cell and Tissue Research
Snail and Slug promote epithelial–mesenchymal transition through β-catenin–TCF-4-dependent expression of TGF-β3
Molecular Biology of the Cell
Beta-catenin is required for endothelial–mesenchymal transformation during heart cushion development in the mouse
Journal of Cell Biology
TGFbeta induces transdifferentiation of iBREC to alphaSMA-expressing cells
International Journal of Molecular Medicine
TGF beta-mediated RhoA expression is necessary for epithelial–mesenchymal transition in the embryonic chick heart
Developmental Dynamics
Snail is required for TGFbeta-induced endothelial–mesenchymal transition of embryonic stem cell-derived endothelial cells
Journal of Cell Science
Ligand-specific function of transforming growth factor beta in epithelial–mesenchymal transition in heart development
Developmental Dynamics
Conversion of vascular endothelial cells into multipotent stem-like cells
Nature Medicine
Transforming growth factor-β2 promotes Snail-mediated endothelial–mesenchymal transition through convergence of Smad-dependent and Smad-independent signalling
Biochemical Journal
Multiple transforming growth factor-beta isoforms and receptors function during epithelial–mesenchymal cell transformation in the embryonic heart
Cells, Tissues, Organs
Endothelial-to-mesenchymal transition contributes to cardiac fibrosis
Nature Medicine
Cited by (176)
Renal intrinsic cells remodeling in diabetic kidney disease and the regulatory effects of SGLT2 Inhibitors
2023, Biomedicine and PharmacotherapyThe driving mechanism and targeting value of mimicry between vascular endothelial cells and tumor cells in tumor progression
2023, Biomedicine and PharmacotherapyThe Kaposi's sarcoma progenitor enigma: KSHV-induced MEndT–EndMT axis
2023, Trends in Molecular MedicineConstruction of tissue-engineered vascular grafts with high patency by mimicking immune stealth and blocking TGF-β mediated endothelial-to-mesenchymal transition
2023, Composites Part B: EngineeringCitation Excerpt :Diminished expression of endothelial junctional proteins including VE-cadherin and CD31 may result in reduced cell–cell contact and increased motility. Indeed, a phenotypic switch from a cobblestone monolayer towards spindly, disorganized fibroblast-like cells is a cardinal feature of ECs undergoing EndMT in vitro [46]. The undesirable EndMT leads to the dysfunction of endothelium and pathological remodeling in TEVGs.
Transcriptomic signatures of individual cell types in cerebral cavernous malformation
2024, Cell Communication and Signaling