AUG 30, 2016 08:00 AM PDT

Disease modeling in pluripotent stem cell-derived cardiomyocytes

Speakers
  • Professor in Stem Cell Biology, University of Nottingham, United Kingdom
    Biography
      Chris Denning is a Professor in Stem Cell Biology, with particular interests in cardiomyocyte (heart cell) differentiation of human embryonic and induced stem cells for use in drug screening and in production of new In vitro models of genetic-based cardiovascular disease. This includes manipulation of the genome using transgenic and nuclease-mediated gene targeting technologies (including Cas9/CRISPR). In parallel, Chris has also focused on optimisation of the culture environment and robotic culture to allow fully automated scale-up and high throughput screening, using high content electrophysiology and imaging.

    Abstract:
    Over the last 15 years, human pluripotent stem cell (hPSC) technologies have progressed from academic curiosities into tools with the promise to underpin commerce, leading to real progress in understanding of disease, improving drug safety and providing novel routes to clinical translation. With an emphasis on the heart, this presentation will discuss our progress in producing models of genetic disease by reprogramming somatic cells into human induced pluripotent stem cell (hiPSC). This includes various conditions such as long QT syndrome, Duchenne muscular dystrophy and CPVT, which affect the function and / or structure of cardiomyocytes. We will show how the Cas9/CRISPR system is being used to produce defined sets of polymorphisms in the ADRB2R and GRK5 loci, which encode proteins that underpin b2-adrenoceptor signaling. These polymorphisms reflect the genotypes in the patient population and we will present early data on how these changes may influence receptor density, internalization and both receptor and heart function. Since these panels of hiPSC and engineered lines can now be created with relative ease, bottlenecks of scaled culture, differentiation and phenotyping are becoming a considerable issue. Thus, we have developed an automation suite that includes a bespoke robotic platform to culture and differentiate hPSCs at scale into cardiomyocytes. Into this suite, we have incorporated high content platforms that allow assessment of structure (confocal plate reader imaging) and function (mitochondrial activity, contractility and electrophysiology). Despite these advances, numerous challenges remain, such as incomplete epigenetic reprogramming of hiPSC relative to hESCs and insufficient levels of expression of key ion channels, which need to be considered for the applicability of these models in biomedical application.
     

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