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Revealing the neuronal phenotypes of Williams syndrome in a dish

  • Author(s): Chailangkarn, Thanathom
  • et al.

The invention of induced pluripotent stem cells (iPSCs) like never before has opened novel opportunity to study diseases in relevant cell types. Within less than 10 years, a variety of diseases such as Rett syndrome, long QT syndrome and spinal muscular atrophy, have been successfully modeled. In this study, Williams syndrome (WS), a rare genetic neurodevelopmental disorder, that is caused by hemizygous deletion of 25 genes on chromosome 7, is of interest because of its unique cognitive and social profiles which are opposite to those of autism spectrum disorders. Despite the extensive studies on WS hypersociability, little is known about haploinsufficiency effect of those genes on molecular and cellular phenotypes in neuronal level due to the lack of relevant human cellular model. Using reprogramming approach, we found that WS iPSC-derived neural progenitor cells has increased apoptosis and therefore increased doubling time. The phenotypes could be rescued by complementation of frizzled9, one of 25 genes typically deleted in WS. Moreover, WS iPSC-derived CTIP2 positive (cortical layer V /VI) pyramidal neurons exhibit morphology alterations including longer total dendrites and increasing dendritic spine number per neuron, which are similarly observed in postmortem layer V/VI neurons. In addition, WS iPSC- derived neurons show an increase in calcium transient frequency likely due to an increase in number of dendritic spines. While we demonstrated that this promising iPSC system could be used to model such multigenic neurodevelopmental disorder, the technology itself still needs to be optimized. Culture medium, one of the most important factors required for maintenance of self-renewal and pluripotency of iPSC, has been developed empirically and claimed as an optimal formulation. We applied design of experiments, a statistic and mathematic tool widely used in engineering and chemical research, to systematically determine the most efficient concentration of final 2 components (basic fibroblast growth factor and neuregulin1) in the culture medium. Compared to commercial medium (mTeSR1), our optimized formulation (iDEAL) for iPSC decreases apoptotic cells, improves pluripotency maintenance, supports no-weekend medium change routine, enhances survival of single-cell passaging as well as reactivates inactive X chromosome upon reprogramming, providing more efficient and suitable condition for iPSCs

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