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Home | Pregnancy Timeline | News Alerts |News Archive Aug 23, 2013

 

vascular endothelial cells

Human induced pluripotent stem cells appear to differentiate
into cells lining arteries or veins in response to the intensity
of blood flow over their surface.

Image credit: Stem Cell Reports, Volume 1, Issue 2, 105-113, 25 July 2013






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Harvard stem cell researchers create cells that line blood vessels

In a scientific first, Harvard Stem Cell Institute scientists have successfully grown cells that line the blood vessels—called vascular endothelial cells—from human induced pluripotent stem cells (iPSCs), revealing new information about how these cells function.

Using a unique approach, researchers induced differentiation of specific cell types by mimicking the flow of blood over the surface of iPSC-generated endothelial cells. Cells that felt a stronger "flow" became artery cells, while those that felt a weaker "flow" became vein cells.


"It was especially exciting to us to discover that these cells are basically responding to biomechanical cues. By exposing cells to 'atheroprone flow,' we can direct differentiation of these cells into cells that are present in areas of the circulatory system we know are affected by diseases like atherosclerosis."

Guillermo García-Cardena, PhD, research leader and HSCI Affiliated Faculty member


García-Cardena is now working on modeling the formation of arterial plaques using human iPSC-derived vascular endothelial cells and identifying potential drugs that might prevent plaque formation.

García-Cardena's team, which included Harvard School of Engineering and Applied Sciences graduate student William Adams, found that the iPS-derived human endothelial cells display three critical functions carried out by mature endothelium in the body: mounting inflammatory responses, keeping blood from leaking out of the blood vessel, and preventing blood clots.

Based on this information, García-Cardena's work, published this month in the journal Stem Cell Reports, has another exciting implication—it could potentially reduce, or even eliminate the need for heparin use during kidney dialysis and lung failure treatment—making both markedly safer.

Traditionally, patients undergoing dialysis are treated with heparin, a powerful drug, which prevents the blood from clotting as it's routed through the dialysis machine. While heparin is quite effective in preventing clotting, because it considerably thins the blood, it can also cause loss of blood, internal bleeding, and interfere with the healing process.

"The iPSC-derived endothelial cells cells beautifully function as an anticoagulant surface," said García-Cardena, an Associate Professor of Pathology at Harvard Medical School and Brigham and Women's Hospital. "In the future, we may take a tissue sample from a patient, generate iPSCs, and then cover an extracorporeal device with the patient's own endothelial cells—so the patient can go home with the device without the need for regular heparin shots."

Abstract-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
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.

The National Institutes of Health funded this research.

Research Cited: Functional Vascular Endothelium Derived from Human Induced Pluripotent Stem Cells. Stem Cell Reports. August 6, 2013

Original press release: http://www.eurekalert.org/pub_releases/2013-08/hu-hsc082213.php