Open AccessRapid neurogenesis through transcriptional activation in human stem cells
Author(s) -
Busskamp Volker,
Lewis Nathan E,
Guye Patrick,
Ng Alex HM,
Shipman Seth L,
Byrne Susan M,
Sanjaeville E,
Murn Jernej,
Li Yinqing,
Li Shangzhong,
Stadler Michael,
Weiss Ron,
Church George M
Publication year - 2014
Publication title -
molecular systems biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 8.523
H-Index - 148
ISSN - 1744-4292
DOI - 10.15252/msb.20145508
Subject(s) - neurogenesis , biology , reprogramming , induced pluripotent stem cell , stem cell , cellular differentiation , progenitor cell , transcription factor , microbiology and biotechnology , microrna , neural stem cell , embryonic stem cell , cell , genetics , gene
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.