Modeling hippocampal neurogenesis using human pluripotent stem cells

Stem Cell Reports. 2014 Feb 27;2(3):295-310. doi: 10.1016/j.stemcr.2014.01.009. eCollection 2014 Mar 11.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials
  • Cell Differentiation
  • Dentate Gyrus / cytology
  • Dentate Gyrus / metabolism
  • Electrophysiological Phenomena
  • Embryoid Bodies / cytology
  • Embryoid Bodies / metabolism
  • Gene Expression
  • Genes, Reporter
  • Hippocampus / cytology*
  • Hippocampus / metabolism*
  • Homeodomain Proteins / metabolism
  • Humans
  • Nerve Net
  • Neural Stem Cells / cytology
  • Neural Stem Cells / metabolism
  • Neurogenesis*
  • Neurons / cytology
  • Neurons / metabolism
  • Neurotransmitter Agents / biosynthesis
  • Pluripotent Stem Cells / cytology*
  • Pyramidal Cells / cytology
  • Pyramidal Cells / metabolism
  • Schizophrenia / metabolism
  • Schizophrenia / physiopathology
  • Tumor Suppressor Proteins / metabolism


  • Homeodomain Proteins
  • Neurotransmitter Agents
  • Tumor Suppressor Proteins
  • prospero-related homeobox 1 protein