modeling of brain development using human neural stem cells extensively parallels
Tuesday, Nov 12, 2013, 11:15 AM -11:30 AM
++A.04.c. Induced pluripotent stem cells and models of disease
*L. DE LA TORRE-UBIETA
, J. L. STEIN, N. N. PARIKSHAK, D. LU, J. K. LOWE, E. WEXLER, D. H. GESCHWIND;
UCLA, Los Angeles, CA
Human neural stem cells are poised to revolutionize our ability to make mechanistic inferences that bridge the gap between traditional model systems and human biology. However, the utility of such systems relies on their capacity to recapitulate key in vivo neurodevelopmental processes. We performed longitudinal transcriptome profiling in differentiating hNPCs over 12 weeks to determine the overlap between in vitro neuronal differentiation and in vivo fetal cortical development at a genome-wide level. Differentiating hNPCs express key telencephalic markers, are enriched in transcriptomically defined cortical regional markers (Brainspan) and undergo stereotypical neuronal morphogenesis with extensive dendritic arborizations (Fig 1A). Gene expression changes closely matched gene expression profiles in developing fetal cortex from embryonic (4-8 post conception weeks [PCW]) to late mid-fetal development (19-24 PCW; Fig 1B). Ten of 16 in vitro gene co-expression modules defined by whole genome co-expression network analysis are highly preserved in vivo (preservation p<3x10-5; Fig 1C). Preserved modules are associated with a variety of neurodevelopmental processes including exit from mitosis, neurogenesis, neurite growth and synaptogenesis. Finally, we assessed the translational potential of the hNPCs for neuropsychiatric disease, in particular ASD. The second most preserved module is related to glutamatergic synaptic function and is enriched in ASD susceptibility genes identified in genetic association studies. Further, we found that an adult human brain module related to synaptic function, previously found to be downregulated in the ASD brain is preserved in vitro in primary hNPCs. These data demonstrate the validity of hNPCs to study the molecular mechanisms of human neurodevelopmental disease pathophysiology, an important advance in stem cell biology and translational neuroscience.
L. De La Torre-Ubieta:
BSCRC Innovation Award
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