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Mash1 and neurogenin 2 enhance survival and differentiation of neural precursor cells after transplantation to rat brains via distinct modes of action.

Authors
Yi, SH; Jo, AY; Park, CH; Koh, HC; Park, RH; Suh-Kim, H; Shin, I; Lee, YS; Kim, J; Lee, SH
Citation
Molecular therapy : the journal of the American Society of Gene Therapy, 16(11):1873-1882, 2008
Journal Title
Molecular therapy : the journal of the American Society of Gene Therapy
ISSN
1525-00161525-0024
Abstract
Neural precursor cells (NPCs) are regarded as a promising source of donor cells in transplantation-based therapies for neurodegenerative disorders. However, poor survival and limited neuronal differentiation of the transplanted NPCs remain critical limitations for developing therapeutic strategies. In this study, we investigated the effects of the proneural basic helix-loop-helix (bHLH) transcription factors Mash1 and Neurogenin 2 (Ngn2) in neuronal differentiation and survival of NPCs. Induction of Mash1 or Ngn2 expression strikingly enhanced neuronal differentiation of cultured NPCs in vitro. Ngn2-transduced NPCs underwent a rapid cell cycle arrest, which often accompanies differentiation. In contrast, cells continuously expanded upon Mash1 expression during NPC differentiation. Notably, sonic hedgehog (SHH) was upregulated by Mash1 and mediated the proliferative and survival effects of Mash1 on NPCs. Upon transplantation into adult rat brains, Mash1-expressing NPCs yielded large grafts enriched with neurons compared to control LacZ-transduced NPCs. Interestingly, enhancements in neuronal yield, as well as in donor cell survival, were also achieved by transplanting Ngn2-transduced NPCs. We show that a differentiation stage- and cell density-dependent survival effect of Ngn2 involves neurotrophin3 (NT3)/TrkC-mediated signaling. Together, these findings suggest potential benefits of bHLH gene manipulation to develop successful transplantation strategies for brain disorders.
MeSH terms
AnimalsBasic Helix-Loop-Helix Transcription Factors/biosynthesisBasic Helix-Loop-Helix Transcription Factors/genetics*Brain/cytologyCell Differentiation/physiology*Cell ProliferationCell Survival/physiology*Cells, CulturedEmbryonic Stem Cells/cytologyEmbryonic Stem Cells/transplantation*Hedgehog Proteins/physiologyMiceNerve Tissue Proteins/biosynthesisNerve Tissue Proteins/genetics*Neurons/cytologyNeurons/transplantation*Neurotrophin 3/physiologyRatsRats, Sprague-DawleySignal TransductionTransduction, Genetic
DOI
10.1038/mt.2008.189
PMID
18781144
Appears in Collections:
Journal Papers > School of Medicine / Graduate School of Medicine > Anatomy
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