Neural differentiation from embryonic stem cells in vitro: An overview of the signaling pathways

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

Figure 1

A simplified scheme outlining the signaling pathways described in the text. The inducers that induce embryonic stem cells to differentiate into neurons reported thus far including RA, Wnt/β-catenin, TGF/BMP, Notch, FGF, cytokine, Hedgehog, JNK/MAPK and others. The inducers in the middle part of figure mediate signaling molecules that bring about the differentiation into neurons. → means stimulation. Some miscellaneous molecules/factors mentioned at the end of this text are not included in this figure. RA: Retinoic acid; TGF: Transforming growth factor; BMP: Bone morphogenetic protein; CREB: cAMP response element-binding protein; Dkk-1: Dickkopf-related protein 1; Erk: Extracellular signal-regulated kinase; FGF: Fibroblast growth factor; Hh: Hedgehog; JAK: Janus kinase; JNK: C-Jun N-terminal kinase; MAPK: Mitogen-activated protein kinase.