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PMID: 24672753 Published · epublish English Journal Article Research Support, Non-U.S. Gov't

Modeling hippocampal neurogenesis using human pluripotent stem cells.

Stem cell reports ·Vol. 2 ·No. 3 ·2014-03-11 ·Pages 295-310

Yu DX, Di Giorgio FP, Yao J, Marchetto MC, Brennand K, Wright R, Mei A, McHenry L, Lisuk D, Grasmick JM, Silberman P, Silberman G, Jappelli R, Gage FH

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.

MeSH Terms
Action Potentials Cell Differentiation Dentate Gyrus/cytology,metabolism Electrophysiological Phenomena Embryoid Bodies/cytology,metabolism Gene Expression Genes, Reporter Hippocampus/cytology,metabolism Homeodomain Proteins/metabolism Humans Nerve Net Neural Stem Cells/cytology,metabolism Neurogenesis Neurons/cytology,metabolism Neurotransmitter Agents/biosynthesis Pluripotent Stem Cells/cytology Pyramidal Cells/cytology,metabolism Schizophrenia/metabolism,physiopathology Tumor Suppressor Proteins/metabolism
Chemicals
Homeodomain Proteins Neurotransmitter Agents Tumor Suppressor Proteins prospero-related homeobox 1 protein
Authors & Affiliations
14 authors, click to expand affiliations / ORCID
Yu Diana Xuan
The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
Di Giorgio Francesco Paolo
Neuroscience Discovery, Novartis Pharma AG, Novartis Institute for Biomedical Research, Postfach, Basel CH-4002, Switzerland.
Yao Jun
The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
Marchetto Maria Carolina
The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
Brennand Kristen
Department of Neuroscience/Psychiatry, Mount Sinai School of Medicine, 1425 Madison Ave, New York, NY 10059, USA.
Wright Rebecca
The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
Mei Arianna
The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
McHenry Lauren
The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
Lisuk David
The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
Grasmick Jaeson Michael
The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
Silberman Pedro
The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
Silberman Giovanna
The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
Jappelli Roberto
The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
Gage Fred H
The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
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Article Info
Journal
Stem cell reports
Abbr.
Stem Cell Reports
ISSN
2213-6711
DOI
10.1016/j.stemcr.2014.01.009
Published
2014-03-11
Epub
2014-00-27
Pages
295-310
Language
English
Region
United States
NLM ID
101611300
PMCID
PMC3964286
Subset
IM
Corrections
ErratumIn
-
External Links
PubMed source DOI: 10.1016/j.stemcr.2014.01.009 PMC Full Text View journal details
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