Ernst Wolvetang*

 

Australian Institute for Bioengineering and Nanotechnology, University of Queensland, Brisbane, St Lucia, QLD, 4072, Australia

 

Investigations into the of etiology neurodegenerative diseases have been frustrated by a lack of access to developing human tissues, and the limited ability of mouse models to recapitulate complex human nervous system diseases, creating a need for new human cellular model systems. We use human induced pluripotent stem cells (hIPSC) as our model system of choice to reveal pathogenic mechanisms of neurological diseases such as Down syndrome (DS), Ataxia-Telangiectasia (A-T) and hypomyelinating diseases (HBSL). We use both directed and guided differentiation of integration-free iPSC as well as trans-differentiation of patient fibroblasts to generate disease relevant cell types such as cortical neurons, astrocytes and cerebellar granule cells. We employ CRISPR based genome manipulation tools to probe the gene regulatory networks underlying pathogenesis (such as in DS), or for generating isogenic controls. In each case our approach is to combine cell phenotypic analyses, neuronal activity reporters, with transcriptome or single cell transcriptome analyses to identify the molecular processes underlying pathogenic phenotypes that can be identified in vitro. Using this strategy, we have interrogated the role of APP in Alzheimers disease-like changes in DS neurons, mitochondrial and calcium handling changes in A-T neurons and cerebellar cells, and myelination in HBSL-iPSC derived oligodendrocyte-cortical neuron co-cultures. We also discovered neuronal activity dependent LncRNAs potentially involved in schizophrenia and epilepsy. Collectively our research provides evidence that iPSCs are useful tools for dissecting the mechanisms of monogenic and complex human neurological diseases and, importantly, testing of therapeutics.

 

Biographic details

Prof Stem Cell Biology, Group leader Stem Cell Engineering Group

Director of UQ Centre for stem cell ageing and regenerative engineering