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      Functional Vascular Endothelium Derived from Human Induced Pluripotent Stem Cells

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          Summary

          Vascular endothelium is a dynamic cellular interface that displays a unique phenotypic plasticity. This plasticity is critical for vascular function and when dysregulated is pathogenic in several diseases. Human genotype-phenotype studies of endothelium are limited by the unavailability of patient-specific endothelial cells. To establish a cellular platform for studying endothelial biology, we have generated vascular endothelium from human induced pluripotent stem cells (iPSCs) exhibiting the rich functional phenotypic plasticity of mature primary vascular endothelium. These endothelial cells respond to diverse proinflammatory stimuli, adopting an activated phenotype including leukocyte adhesion molecule expression, cytokine production, and support for leukocyte transmigration. They maintain dynamic barrier properties responsive to multiple vascular permeability factors. Importantly, biomechanical or pharmacological stimuli can induce pathophysiologically relevant atheroprotective or atheroprone phenotypes. Our results demonstrate that iPSC-derived endothelium possesses a repertoire of functional phenotypic plasticity and is amenable to cell-based assays probing endothelial contributions to inflammatory and cardiovascular diseases.

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          Highlights

          • Human iPSCs generate vascular ECs with a rich functional repertoire
          • iPSC-ECs can undergo endothelial activation and maintain dynamic permeability
          • Biomechanical forces direct iPSC-ECs to atheroprotective or atheroprone phenotypes
          • iPSC-ECs are directed to an atheroprotective phenotype via pharmacological stimulus

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          Most cited references 37

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          Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors.

          Differentiated cells can be reprogrammed to an embryonic-like state by transfer of nuclear contents into oocytes or by fusion with embryonic stem (ES) cells. Little is known about factors that induce this reprogramming. Here, we demonstrate induction of pluripotent stem cells from mouse embryonic or adult fibroblasts by introducing four factors, Oct3/4, Sox2, c-Myc, and Klf4, under ES cell culture conditions. Unexpectedly, Nanog was dispensable. These cells, which we designated iPS (induced pluripotent stem) cells, exhibit the morphology and growth properties of ES cells and express ES cell marker genes. Subcutaneous transplantation of iPS cells into nude mice resulted in tumors containing a variety of tissues from all three germ layers. Following injection into blastocysts, iPS cells contributed to mouse embryonic development. These data demonstrate that pluripotent stem cells can be directly generated from fibroblast cultures by the addition of only a few defined factors.
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            Inflammation, atherosclerosis, and coronary artery disease.

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              Effects of disturbed flow on vascular endothelium: pathophysiological basis and clinical perspectives.

              Vascular endothelial cells (ECs) are exposed to hemodynamic forces, which modulate EC functions and vascular biology/pathobiology in health and disease. The flow patterns and hemodynamic forces are not uniform in the vascular system. In straight parts of the arterial tree, blood flow is generally laminar and wall shear stress is high and directed; in branches and curvatures, blood flow is disturbed with nonuniform and irregular distribution of low wall shear stress. Sustained laminar flow with high shear stress upregulates expressions of EC genes and proteins that are protective against atherosclerosis, whereas disturbed flow with associated reciprocating, low shear stress generally upregulates the EC genes and proteins that promote atherogenesis. These findings have led to the concept that the disturbed flow pattern in branch points and curvatures causes the preferential localization of atherosclerotic lesions. Disturbed flow also results in postsurgical neointimal hyperplasia and contributes to pathophysiology of clinical conditions such as in-stent restenosis, vein bypass graft failure, and transplant vasculopathy, as well as aortic valve calcification. In the venous system, disturbed flow resulting from reflux, outflow obstruction, and/or stasis leads to venous inflammation and thrombosis, and hence the development of chronic venous diseases. Understanding of the effects of disturbed flow on ECs can provide mechanistic insights into the role of complex flow patterns in pathogenesis of vascular diseases and can help to elucidate the phenotypic and functional differences between quiescent (nonatherogenic/nonthrombogenic) and activated (atherogenic/thrombogenic) ECs. This review summarizes the current knowledge on the role of disturbed flow in EC physiology and pathophysiology, as well as its clinical implications. Such information can contribute to our understanding of the etiology of lesion development in vascular niches with disturbed flow and help to generate new approaches for therapeutic interventions.
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                Author and article information

                Contributors
                Journal
                Stem Cell Reports
                Stem Cell Reports
                Stem Cell Reports
                Elsevier
                2213-6711
                25 July 2013
                25 July 2013
                06 August 2013
                : 1
                : 2
                : 105-113
                Affiliations
                [1 ]Center for Excellence in Vascular Biology, Department of Pathology, Brigham and Women’s Hospital, Boston, MA 02115, USA
                [2 ]Program in Developmental and Regenerative Biology, Harvard Medical School, Boston, MA 02115, USA
                [3 ]Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA 02115, USA
                [4 ]School of Engineering and Applied Sciences, Harvard University, Cambridge, MA 02138, USA
                [5 ]Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA
                Author notes
                Article
                S2213-6711(13)00049-0
                10.1016/j.stemcr.2013.06.007
                3757754
                24052946
                © 2013 The Authors

                This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-No Derivative Works License, which permits non-commercial use, distribution, and reproduction in any medium, provided the original author and source are credited.

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