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NOV 09, 2017 4:00 AM PST

Human pluripotent stem cells in understanding genetic cardiovascular disease and effects of drugs

Speaker
  • Chair of Anatomy and Embryology and Professor of Developmental Biology, Leiden University Medical Center
    Biography
      Christine Mummery is Chair of Anatomy and Embryology and Professor of Developmental Biology at Leiden University Medical Center. Her research concerns cardiovascular development and disease models based on human pluripotent stem cells. Immediate interests are on developing biophysical techniques for characterization and functional analysis of cardiovascular cells from hPSC. In 2015 she became guest professor at the Technical University of Twente to develop organ-on-chip models. Dr. Mummery is a member of the Royal Netherlands Academy of Science, on the board of the Netherlands Medical Research Council and holds a European Research Council Advanced Grant to study cardiac development and disease in humans based on stem cell models. She wrote a lay-guide on stem cells "Stem Cell: Scientific Facts and Fiction" (Elsevier 2014) and is Editor-in-Chief of Stem Cell Reports, the journal of the International Society of Stem Cell Research. She is also on the editorial boards of Cell Stem Cell, Cardiovascular Research and Stem Cells.

    Abstract

    Derivation of many different cell types from human pluripotent stem cells (embryonic stem cells or HESCs and induced pluripotent stem cells or hiPS cells) is an area of growing interest both for potential cell therapy and as a platform for drug discovery and toxicity. Most particularly, the recent availability of methods to introduce specific disease mutations into human pluripotent stem cells and/or to derive these cells as hiPS cells by reprogramming from any patient of choice, are creating unprecedented opportunities to create disease models “in a dish” and study ways to treat it or slow down its rate of development. Understanding the underlying developmental mechanisms that control differentiation of pluripotent cells to their derivatives and mimicking these in defined culture conditions in vitro is now essential for moving the field forward. We have used these methods to produce isogenic pairs of hiPSC lines to compare diseased and corresponding control cardiomyocytes and vascular endothelial cells and identify disease related phenotypes and mechanisms. The use of isogenic pairs has proved crucial since variability between “healthy control” hiPSC lines is often greater than the difference between a diseased cells and its isogenic control.  We have also examined drug responses of hESC-derived cardiomyocytes to a variety of cardiac and non-cardiac drugs and shown that iPSC derived cardiomyocytes with mutations in ion channel genes can accurately predict changes in cardiac electrical properties and reveal drug sensitivities also observed in patients. Similar studies will be described using vascular endothelial cells from hPSC. Relevant in all cases is the development of appropriate bioassays in which to measure disease phenotypes which may be highly cell type specific dependent. For heart cells, this might be electrical activity or contractions force; for vascular cells, responses to fluid flow flow and inflammation. Various approaches to this will be presented.


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