Generation of Dopamine Neurons from Rodent Fibroblasts through the Expandable Neural Precursor Cell Stage

Title
Generation of Dopamine Neurons from Rodent Fibroblasts through the Expandable Neural Precursor Cell Stage
Authors
김진혁
Keywords
EMBRYONIC STEM-CELLS; IN-VITRO; MOUSE FIBROBLASTS; DIRECT CONVERSION; MICROGLIAL ACTIVATION; GENE-EXPRESSION; DEFINED FACTORS; SOMATIC-CELLS; DIFFERENTIATION; ISCHEMIA
Issue Date
2015-07
Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
Citation
JOURNAL OF BIOLOGICAL CHEMISTRY, v. 290, NO 28, Page. 17401-17414
Abstract
Recent groundbreaking work has demonstrated that combined expression of the transcription factors Brn2, Ascl1, and Myt1L (BAM; also known as Wernig factors) convert mouse fibroblasts into postmitotic neuronal cells. However, questions remain regarding whether trans-conversion is achieved directly or involves an intermediary precursor stage. Trans-conversion toward expandable neural precursor cells (NPCs) is more useful than direct one-step neuron formation with respect to yielding a sufficient number of cells and the feasibility of manipulating NPC differentiation toward certain neuron subtypes. Here, we show that co-expression of Wernig factors and Bcl-xL induces fibroblast conversion into NPCs (induced NPCs (iNPCs)) that are highly expandable for > 100 passages. Gene expression analyses showed that the iNPCs exhibited high expression of common NPC genes but not genes specific to defined embryonic brain regions. This finding indicated that a regional identity of iNPCs was not established. Upon induction, iNPCs predominantly differentiated into astrocytes. However, the differentiation potential was not fixed and could be efficiently manipulated into general or specific subtypes of neurons by expression of additional genes. Specifically, overexpression of Nurr1 and Foxa2, transcription factors specific for midbrain dopamine neuron development, drove iNPCs to yield mature midbrain dopamine neurons equipped with presynaptic DA neuronal functions. We further assessed the therapeutic potential of iNPCs in Parkinson disease model rats.
URI
http://www.jbc.org/content/290/28/17401.shorthttp://hdl.handle.net/20.500.11754/26201
ISSN
0021-9258; 1083-351X
DOI
http://dx.doi.org/10.1074/jbc.M114.629808
Appears in Collections:
COLLEGE OF MEDICINE[S](의과대학) > MEDICINE(의학과) > Articles
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