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World J Stem Cells. Mar 26, 2015; 7(2): 437-447
Published online Mar 26, 2015. doi: 10.4252/wjsc.v7.i2.437
Neural differentiation from embryonic stem cells in vitro: An overview of the signaling pathways
Jen-Hua Chuang, Li-Chu Tung, Yenshou Lin
Jen-Hua Chuang, Li-Chu Tung, Yenshou Lin, Department of Life Science, National Taiwan Normal University, Taipei 116, Taiwan
Author contributions: Chuang JH, Tung LC and Lin Y conceived and wrote the manuscript; Lin Y revised and finalized the manuscript.
Supported by National Science Council, No. NSC101-2311-B-003-005 and NSC102-2311-B-003-003; National Taiwan Normal University, No. 103T3040B06, 103T3040C06 and 104T3040C06.
Conflict-of-interest: The authors have declared no conflict of interest.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Dr. Yenshou Lin, Associate Professor, Department of Life Science, National Taiwan Normal University, 88, Ting-Chou Road, Section 4, Taipei 116, Taiwan. yenshoulin@ntnu.edu.tw
Telephone: +886-2-77346343 Fax: +886-2-29312904
Received: July 17, 2014
Peer-review started: July 18, 2014
First decision: August 28, 2014
Revised: September 12, 2014
Accepted: December 16, 2014
Article in press: December 16, 2014
Published online: March 26, 2015
Processing time: 245 Days and 17.7 Hours
Abstract

Neurons derived from embryonic stem cells (ESCs) have gained great merit in both basic research and regenerative medicine. Here we review and summarize the signaling pathways that have been reported to be involved in the neuronal differentiation of ESCs, particularly those associated with in vitro differentiation. The inducers and pathways explored include retinoic acid, Wnt/β-catenin, transforming growth factor/bone morphogenetic protein, Notch, fibroblast growth factor, cytokine, Hedgehog, c-Jun N-terminal kinase/mitogen-activated protein kinase and others. Some other miscellaneous molecular factors that have been reported in the literature are also summarized and discussed. These include calcium, calcium receptor, calcineurin, estrogen receptor, Hox protein, ceramide, glycosaminioglycan, ginsenoside Rg1, opioids, two pore channel 2, nitric oxide, chemically defined medium, cell-cell interactions, and physical stimuli. The interaction or crosstalk between these signaling pathways and factors will be explored. Elucidating these signals in detail should make a significant contribution to future progress in stem cell biology and allow, for example, better comparisons to be made between differentiation in vivo and in vitro. Of equal importance, a comprehensive understanding of the pathways that are involved in the development of neurons from ESCs in vitro will also accelerate their application as part of translational medicine.

Keywords: Neurons; Differentiation; Embryonic stem cells; Signaling; Pathways

Core tip: Neurons are derived from embryonic stem cells (ESCs) and have been a focus of research recently, particularly because of their application in regenerative medicine. Here we review and summarize the signaling pathways that have been reported to be involved in neuronal differentiation of ESCs, mainly in vitro. The inducers and pathways explored include retinoic acid, Wnt/β-catenin, transforming growth factor/bone morphogenetic protein, Notch, fibroblast growth factor, cytokine, Hedgehog, c-Jun N-terminal kinase/mitogen-activated protein kinase and others. Some miscellaneous factors are also explored. Elucidating these signals in detail should make a significant contribution to future progress in stem cell biology and should also accelerate the application of stem cells in translational medicine.