Rapid neurogenesis through transcriptional activation in human stem cells

Volker Busskamp, Nathan E. Lewis, Patrick Guye, Alex Hm Ng, Seth L. Shipman, Susan M. Byrne, Neville E. Sanjana, Jernej Murn, Yinqing Li, Shangzhong Li, Michael Stadler, Ron Weiss, George M. Church

Research output: Contribution to journalJournal articleResearchpeer-review

Abstract

Advances in cellular reprogramming and stem cell differentiation now enable ex vivo studies of human neuronal differentiation. However, it remains challenging to elucidate the underlying regulatory programs because differentiation protocols are laborious and often result in low neuron yields. Here, we overexpressed two Neurogenin transcription factors in human- induced pluripotent stem cells and obtained neurons with bipolar morphology in 4 days, at greater than 90% purity. The high purity enabled mRNA and microRNA expression profiling during neurogenesis,thus revealing the genetic programs involved in the rapid transition from stem cell to neuron. The resulting cells exhibited transcriptional, morphological and functional signatures of differentiated neurons, with greatest transcriptional similarity to prenatal human brain samples. Our analysis revealed a network of key transcription factors and microRNAs that promoted loss of pluripotency and rapid neurogenesis via progenitor states. Perturbations of key transcription factors affected homogeneity and phenotypic properties of the resulting neurons, suggesting that a systems-level view of the molecular biology of differentiation may guide subsequent manipulation of human stem cells to rapidly obtain diverse neuronal types.
Original languageEnglish
Article number760
JournalMolecular Systems Biology
Volume10
Issue number11
Number of pages22
ISSN1744-4292
DOIs
Publication statusPublished - 2014
Externally publishedYes

Keywords

  • Gene regulatory networks
  • microRNAs
  • Neurogenesis
  • Cellular Reprogramming
  • Stem cell differentiation
  • Transcriptomics

Cite this

Busskamp, V., Lewis, N. E., Guye, P., Ng, A. H., Shipman, S. L., Byrne, S. M., Sanjana, N. E., Murn, J., Li, Y., Li, S., Stadler, M., Weiss, R., & Church, G. M. (2014). Rapid neurogenesis through transcriptional activation in human stem cells. Molecular Systems Biology, 10(11), [760]. https://doi.org/10.15252/msb.20145508