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Disease modelling with human pluripotent stem cells: general principles and specific applications to obesity

Speaker
  • Principal Investigator, University of Cambridge
    Biography
      Florian T. Merkle received his B.S. in biology from the California Institute of Technology (Caltech), which he attended on full tuition merit scholarship. Florian pursued his Ph.D. neuroscience at the University of California, San Francisco (UCSF), where he studied adult neurogenesis in the laboratory of Prof. Arturo Alvarez-Buylla. His work revealed the embryonic origin of adult neural stem cells, overturned the widely-held belief that these stem cells are homogeneous and multipotent, and discovered several new types of adult-born cell types. As a postdoctoral fellow at Harvard University, Florian worked with Prof. Alex Schier and Prof. Kevin Eggan to develop gene editing tools in human pluripotent stem cells (hPSCs) and to sequence and bank a large collection of hPSCs to facilitate disease modelling and transplantation studies. He developed novel methods to differentiate hPSCs into hypothalamic neurons that regulate essential physiological processes and are therefore pivotally important for human health, and whose abnormal function causes a range of diseases including obesity. Florian now leads a research group at the University of Cambridge where he is studying obesity using in vitro disease models and pursuing questions relating to the genetic stability of hPSCs. These studies are supported by the Wellcome Trust, Royal Society, and Academy of Medical Sciences.

    Abstract

    The capacity to generate disease-relevant cell populations from human pluripotent stem cells has tremendous potential for shedding light on human disease mechanisms. I will discuss basic principles of in vitro disease modelling, including the generation of isogenic models with CRISPR/Cas9, the issue of recurrent culture-acquired mutations and how to assess stem cell genomic integrity, and cell type maturity and phenotyping strategies. To frame these issues, I will discuss my research group's interest in obesity, which is largely a disease of excess food intake, which is in turn regulated by neurons in the hypothalamus. We use human stem cell-derived hypothalamic neurons to gain insight into the environmental and genetic factors that alter neuron function.


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