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Modeling hippocampal neurogenesis using human pluripotent stem cells

Yu, DX and Di Giorgio, FP and Yao, J and Marchetto, MC and Brennand, K and Wright, R and Mei, A and McHenry, L and Lisuk, D and Grasmick, JM and Silberman, P and Silberman, G and Jappelli, R and Gage, FH (2014) Modeling hippocampal neurogenesis using human pluripotent stem cells. Stem Cell Reports. pp. 295-310.

Abstract

The availability of human pluripotent stem cells (hPSCs) offers the opportunity to generate lineage-specific cells to investigate mechanisms of human diseases specific to brain regions. Here, we report a differentiation paradigm for hPSCs that enriches for hippocampal dentate gyrus (DG) granule neurons. This differentiation paradigm recapitulates the expression patterns of key developmental genes during hippocampal neurogenesis, exhibits characteristics of neuronal network maturation, and produces PROX1+ neurons that functionally integrate into the DG. Because hippocampal neurogenesis has been implicated in schizophrenia (SCZD), we applied our protocol to SCZD patient-derived human induced pluripotent stem cells (hiPSCs). We found deficits in the generation of DG granule neurons from SCZD hiPSC-derived hippocampal NPCs with lowered levels of NEUROD1, PROX1, and TBR1, reduced neuronal activity, and reduced levels of spontaneous neurotransmitter release. Our approach offers important insights into the neurodevelopmental aspects of SCZD and may be a promising tool for drug screening and personalized medicine. 2014 The Authors

Item Type: Article
Additional Information: NIBR author: Di Giorgio, FP institute: NIBR contributor address: (Yu, Yao, Marchetto, Wright, Mei, McHenry, Lisuk, Grasmick, Silberman, Silberman, Jappelli, Gage) Salk Institute for Biological Studies, 10010 North Torrey Pines Road, San Diego, CA 92037, United States (Di Giorgio) Neuroscience Discovery, Novartis Pharma AG, Novartis Institute for Biomedical Research, Postfach, Basel CH-4002, Switzerland (Brennand) Department of Neuroscience/Psychiatry, Mount Sinai School of Medicine, 1425 Madison Ave, New York, NY 10059, United States
Date Deposited: 13 Oct 2015 13:12
Last Modified: 13 Oct 2015 13:12
URI: https://oak.novartis.com/id/eprint/22632

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