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July 11, 2017

Truly Functional Arterial Cells Reportedly Created for the First Time

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    Arterial endothelial cells derived from human pluripotent stem cells express activated NOTCH1 (in red, which is an arterial endothelial cell marker) and CD144 (in white, which is a pan endothelial cell marker). [The Morgridge Institute for Research]

    Scientists at the Morgridge Institute for Research and the University of Wisconsin-Madison say they have produced, for the first time, functional arterial cells at both the quality and scale to be relevant for disease modeling and clinical application.

    The researchers working in the lab of James Thomson, VMD, Ph.D., report their study (“Functional Characterization of Human Pluripotent Stem Cell-Derived Arterial Endothelial Cells”) in Proceedings of the National Academy of Sciences and describe methods for generating and characterizing arterial endothelial cells that exhibit many of the specific functions required by the body. Furthermore, these cells contributed both to new artery formation and improved survival rate in mice used as a model for myocardial infarction, according to the research team. Mice treated with this cell line had an 83% survival rate, compared to 33% for controls.

    "The cardiovascular diseases that kill people mostly affect the arteries, and no one has been able to make those kinds of cells efficiently before," says Jue Zhang, Ph.D., a Morgridge assistant scientist and lead author. "The key finding here is a way to make arterial endothelial cells more functional and clinically useful."

    The challenge is that generic endothelial cells are relatively easy to create, but they lack true arterial properties and thus have little clinical value, adds Dr. Zhang.

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    Morgridge Institute Regenerative biology researchers Jue Zhang and Matt Brown examine a part for a new bioreactor designed to help grow arterial tissue. [The Morgridge Institute for Research]

    The research team applied two pioneering technologies to the project. First, they used single-cell RNA sequencing to identify the signaling pathways critical for arterial endothelial cell differentiation. They found about 40 genes of optimal relevance. Second, they used CRISPR/Cas9 gene-editing technology that allowed them to create reporter cell lines to monitor arterial differentiation in real time.

    “Single-cell RNA-seq provides information in single-cell resolution that cannot be achieved by traditional bulk RNA-seq, so it can identify novel factors that can be used for promoting arterial endothelial cell differentiation,” Dr. Zhang tells GEN. “CRISPR/Cas9 enables us to generate the reporter cell line in a much more simple and efficient way. The reporter cell reported here is the first human reported cell line that can be used to monitor arterial differentiation.”

    According to Dr. Zhang, using this approach allows scientists to test the function of candidate genes and measure what percentage of cells are “generating into our target arterial cells."

    The research group developed a protocol around five key growth factors that make the strongest contributions to arterial cell development. They also identified some very common growth factors used in stem cell science, such as insulin, that surprisingly inhibit arterial endothelial cell differentiation.

    "Our ultimate goal is to apply this improved cell derivation process to the formation of functional arteries that can be used in cardiovascular surgery," says Dr. Thomson, who is director of regenerative biology at Morgridge and UW-Madison professor of cell and regenerative biology. "This work provides valuable proof that we can eventually get a reliable source for functional arterial endothelial cells and make arteries that perform and behave like the real thing."

    In many cases with vascular disease, patients lack suitable tissue from their own bodies for use in bypass surgeries. And growing arteries from an individual patient's stem cells would be cost prohibitive and take too long to be clinically useful. The challenge will be not only to produce the arteries, but find ways to insure they are compatible and not rejected by patients.

    "Now that we have a method to create these cells, we hope to continue the effort using a more universal donor cell line," continues Dr. Zhang. The lab will focus on cells banked from a unique population of people who are genetically compatible donors for a majority of the population.

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