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Review
. 2012 Apr 10;125(14):1795-808.
doi: 10.1161/CIRCULATIONAHA.111.040352.

Epithelial-to-mesenchymal and endothelial-to-mesenchymal transition: from cardiovascular development to disease

Jason C Kovacic  1 , Nadia Mercader, Miguel Torres, Manfred Boehm, Valentin Fuster
Affiliations
Review

Epithelial-to-mesenchymal and endothelial-to-mesenchymal transition: from cardiovascular development to disease

Jason C Kovacic et al. Circulation. .
No abstract available

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Figures

Figure 1
Figure 1
Organ formation occurs via EMT/MET. Embryonic cells from the epiblast layer (a single layer of epithelial cells) give rise to mesodermal cells via primary EMT. Definitive organ formation then ensues via secondary EMT and successive rounds of EMT-MET. Differing regions of the mesodermal layer give rise to differing organs/structures: the heart, circulatory system and hematopoietic cells arise from lateral plate mesoderm; the urogenital system from intermediate mesoderm; the axial skeleton and skeletal muscle from paraxial mesoderm, and; the primitive notochord (which becomes the nucleus pulposus of intervertebral discs in the adult human) from the axial (midline) mesoderm. This figure depicts cardiac formation. EMT-MET is also involved with endoderm and ectoderm tissue/organ formation.
Figure 2
Figure 2
Key aspects of the molecular and cellular changes that occur with EMT. Abbreviations not previously defined: BM, basement membrane.
Figure 3
Figure 3
Classification of EMT. Type 1 EMT is highly regulated and is associated with embryonic implantation an organ formation. Type 1 EMT may be sub-classified into primary (cells giving rise to EMT for the first time), secondary and tertiary; with these latter forms involved in the successive waves of EMT-MET leading to definitive organ formation. Type 2 EMT is associated with inflammation and fibrosis, and is now increasingly recognized in adult pathologic conditions. Type 3 EMT is involved with malignant cell transformation, including the acquisition of invasive metastatic cellular properties. As distinct from type 1, neither type 2 or type 3 EMT adhere to any higher-order program of spatial or temporal restriction.
Figure 4
Figure 4
Origin and fate of epicardial-derived cells (EPDCs). (A) mRNA in situ hybridization (ISH) for tbx18 on zebrafish sagittal heart sections marking epicardial cells (blue staining). Additional immunostaining against myosin heavy chain was performed to identify myocardium (brown staining) and is shown in the lower panels (e – g). These panels show the progressive developmental sequence of epicardial formation in zebrafish, with vertically matched panels taken from the same developmental stage (a, 2 days postfertilization (dpf); b and e 3 dpf; c and f, 4 dpf; d and g, 5 dpf). Proepicardium (PEO), Epicardium (Epi), Heart Tube (HT), Ventricle (V), Atrium (A). (B) Epicardial EMT during zebrafish regeneration. (a, c) anti-GFP immunohistochemistry on adult zebrafish heart sections from the transgenic ET-27 line, expressing GFP constitutively in all epicardial cells (brown staining). (b, d) ISH on sections of cryoinjured Tg(wt1b:GFP) zebrafish hearts, in which GFP is reactivated in the epicardium upon damage (blue staining). Dorsal is to the top (a) The control heart reveals a single layer of GFP-positive cells on the ventricular surface. (b) Upon cryoinjury, the epicardium thickens as a consequence of injury-induced EMT. (c) 20× enlargement of control heart. (d) 20× enlargement of injured heart. Images acquired at Centro Nacional de Investigaciones Cardiovasculares (Madrid, Spain) by the group of Nadia Mercader.
Figure 5
Figure 5
EndMT contributes to cardiac fibrosis as demonstrated by confocal microscopy with immunofluorescence double-label staining. (A) Aortic banding was used as a rodent model of cardiac hypertrophy/fibrosis. Mice used in these studies were Tie1Cre;R26RstoplacZ, in which all cells of endothelial origin are permanently marked by β-gal expression. Staining was performed with antibodies against β-gal (red) and S100A4, a fibroblast marker (green). Arrows indicate colocalization of β-gal and FSP1 expression involving both microvessels (left) and arterioles (right), indicative of endothelial-derived cells that have undergone EndMT and adopted a fibroblast-like phenotype. Scale bars, 20 μm. Figure reproduced with permission from Zeisberg et al.(B) EndMT in cardiac fibrosis shown by co-expression of endothelial (CD31 - red) and fibroblast (S100A4 - green) markers. Z-stack images showed specific overlay of double immunostaining for CD31 and S100A4. Nuclear staining is shown in blue (DAPI). Figure reproduced with permission from Widyantoro et al.
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References

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