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Stem Cells Transl Med. 2014 Jun;3(6):713-22. doi: 10.5966/sctm.2013-0111. Epub 2014 Apr 15.

Signaling adaptor protein SH2B1 enhances neurite outgrowth and accelerates the maturation of human induced neurons.

Author information

1
Division of Regenerative Medicine, Institute of Cellular and System Medicine, and Center for Neuropsychiatric Research, National Health Research Institutes, Miaoli, Taiwan, Republic of China; Graduate Program of Biotechnology in Medicine, Institute of Biotechnology and Department of Life Science, Institute of Molecular Medicine, and Department of Medical Science, National Tsing Hua University, Hsinchu, Taiwan, Republic of China; Department of Psychiatry, Chang Gung Memorial Hospital at Linkou and Chang Gung University, Gueishan, Taoyuan, Taiwan, Republic of China; Department of Pharmacology, Tzu Chi University, Hualien, Taiwan, Republic of China; Department of Life Sciences, National Chung Hsing University, Taichung, Taiwan, Republic of China.
2
Division of Regenerative Medicine, Institute of Cellular and System Medicine, and Center for Neuropsychiatric Research, National Health Research Institutes, Miaoli, Taiwan, Republic of China; Graduate Program of Biotechnology in Medicine, Institute of Biotechnology and Department of Life Science, Institute of Molecular Medicine, and Department of Medical Science, National Tsing Hua University, Hsinchu, Taiwan, Republic of China; Department of Psychiatry, Chang Gung Memorial Hospital at Linkou and Chang Gung University, Gueishan, Taoyuan, Taiwan, Republic of China; Department of Pharmacology, Tzu Chi University, Hualien, Taiwan, Republic of China; Department of Life Sciences, National Chung Hsing University, Taichung, Taiwan, Republic of China ingming@nhri.org.tw.

Abstract

Recent advances in somatic cell reprogramming have highlighted the plasticity of the somatic epigenome, particularly through demonstrations of direct lineage reprogramming of adult mouse and human fibroblasts to induced pluripotent stem cells (iPSCs) and induced neurons (iNs) under defined conditions. However, human cells appear to be less plastic and have a higher epigenetic hurdle for reprogramming to both iPSCs and iNs. Here, we show that SH2B adaptor protein 1β (SH2B1) can enhance neurite outgrowth of iNs reprogrammed from human fibroblasts as early as day 14, when combined with miR124 and transcription factors BRN2 and MYT1L (IBM) under defined conditions. These SH2B1-enhanced iNs (S-IBM) showed canonical neuronal morphology, and expressed multiple neuronal markers, such as TuJ1, NeuN, and synapsin, and functional proteins for neurotransmitter release, such as GABA, vGluT2, and tyrosine hydroxylase. Importantly, SH2B1 accelerated mature process of functional neurons and exhibited action potentials as early as day 14; without SH2B1, the IBM iNs do not exhibit action potentials until day 21. Our data demonstrate that SH2B1 can enhance neurite outgrowth and accelerate the maturation of human iNs under defined conditions. This approach will facilitate the application of iNs in regenerative medicine and in vitro disease modeling.

KEYWORDS:

Neural differentiation; Neural induction; Neuron; Reprogramming; SH2B1

PMID:
24736401
PMCID:
PMC4039450
DOI:
10.5966/sctm.2013-0111
[Indexed for MEDLINE]
Free PMC Article

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