title: Signaling adaptor protein SH2B1 enhances neurite outgrowth and accelerates the maturation of human induced neurons.
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.
authors.affiliation: 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.
authors.forename: Yi-Chao
authors.initials: YC
authors.lastname: Hsu
authors.affiliation: 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.
authors.forename: Su-Liang
authors.initials: SL
authors.lastname: Chen
authors.affiliation: 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.
authors.forename: Ya-Jean
authors.initials: YJ
authors.lastname: Wang
authors.affiliation: 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.
authors.forename: Yun-Hsiang
authors.initials: YH
authors.lastname: Chen
authors.affiliation: 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.
authors.forename: Dan-Yen
authors.initials: DY
authors.lastname: Wang
authors.affiliation: 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.
authors.forename: Linyi
authors.initials: L
authors.lastname: Chen
authors.affiliation: 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.
authors.forename: Chia-Hsiang
authors.initials: CH
authors.lastname: Chen
authors.affiliation: 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.
authors.forename: Hwei-Hsien
authors.initials: HH
authors.lastname: Chen
authors.affiliation: 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.
authors.forename: Ing-Ming
authors.initials: IM
authors.lastname: Chiu
mesh_terms: D000200:Action Potentials; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D015415:Biomarkers / Q000378:metabolism; D048430:Cell Shape; D002478:Cells, Cultured; D065150:Cellular Reprogramming; D005838:Genotype; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D058953:Neural Stem Cells / Q000378:metabolism*; D016501:Neurites / Q000378:metabolism*; D055495:Neurogenesis; D009474:Neurons / Q000378:metabolism*; D050809:POU Domain Factors / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D044968:Regenerative Medicine / Q000379:methods*; D013997:Time Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014162:Transfection
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D015415:Biomarkers; D018398:Homeodomain Proteins; C561020:MYT1L protein, human; D009419:Nerve Tissue Proteins; D050809:POU Domain Factors; C518910:SH2B1 protein, human; D014157:Transcription Factors; C085076:transcription factor Brn-2
keywords: Neural differentiation; Neural induction; Neuron; Reprogramming; SH2B1
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