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Dynamic Trk and G Protein Signalings Regulate Dopaminergic Neurodifferentiation in Human Trophoblast Stem Cells

Understanding the mechanisms in the generation of neural stem cells from pluripotent stem cells is a fundamental step towards successful management of neurodegenerative diseases in translational medicine. Albeit all-trans retinoic acid (RA) has been associated with axon outgrowth and nerve regenerat...

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Autores principales: Tsai, Eing-Mei, Wang, Yu-Chih, Lee, Tony Tung-Yin, Tsai, Cheng-Fang, Chen, Hung-Sheng, Lai, Feng-Jie, Yokoyama, Kazunari K., Hsieh, Tsung-Hsun, Wu, Ruey-Meei, Lee, Jau-nan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4659658/
https://www.ncbi.nlm.nih.gov/pubmed/26606046
http://dx.doi.org/10.1371/journal.pone.0143852
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author Tsai, Eing-Mei
Wang, Yu-Chih
Lee, Tony Tung-Yin
Tsai, Cheng-Fang
Chen, Hung-Sheng
Lai, Feng-Jie
Yokoyama, Kazunari K.
Hsieh, Tsung-Hsun
Wu, Ruey-Meei
Lee, Jau-nan
author_facet Tsai, Eing-Mei
Wang, Yu-Chih
Lee, Tony Tung-Yin
Tsai, Cheng-Fang
Chen, Hung-Sheng
Lai, Feng-Jie
Yokoyama, Kazunari K.
Hsieh, Tsung-Hsun
Wu, Ruey-Meei
Lee, Jau-nan
author_sort Tsai, Eing-Mei
collection PubMed
description Understanding the mechanisms in the generation of neural stem cells from pluripotent stem cells is a fundamental step towards successful management of neurodegenerative diseases in translational medicine. Albeit all-trans retinoic acid (RA) has been associated with axon outgrowth and nerve regeneration, the maintenance of differentiated neurons, the association with degenerative disease like Parkinson's disease, and its regulatory molecular mechanism from pluripotent stem cells to neural stem cells remain fragmented. We have previously reported that RA is capable of differentiation of human trophoblast stem cells to dopamine (DA) committed progenitor cells. Intracranial implantation of such neural progenitor cells into the 6-OHDA-lesioned substantia nigra pars compacta successfully regenerates dopaminergic neurons and integrity of the nigrostriatal pathway, ameliorating the behavioral deficits in the Parkinson’s disease rat model. Here, we demonstrated a dynamic molecular network in systematic analysis by addressing spatiotemporal molecular expression, intracellular protein-protein interaction and inhibition, imaging study, and genetic expression to explore the regulatory mechanisms of RA induction in the differentiation of human trophoblast stem cells to DA committed progenitor cells. We focused on the tyrosine receptor kinase (Trk), G proteins, canonical Wnt2B/β-catenin, genomic and non-genomic RA signaling transductions with Tyrosine hydroxylase (TH) gene expression as the differentiation endpoint. We found that at the early stage, integration of TrkA and G protein signalings aims for axonogenesis and morphogenesis, involving the novel RXRα/Gα(q/11) and RARβ/Gβ signaling pathways. While at the later stage, five distinct signaling pathways together with epigenetic histone modifications emerged to regulate expression of TH, a precursor of dopamine. RA induction generated DA committed progenitor cells in one day. Our results provided substantial mechanistic evidence that human trophoblast stem cell-derived neural stem cells can potentially be used for neurobiological study, drug discovery, and as an alternative source of cell-based therapy in neurodegenerative diseases like Parkinson’s disease.
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spelling pubmed-46596582015-12-02 Dynamic Trk and G Protein Signalings Regulate Dopaminergic Neurodifferentiation in Human Trophoblast Stem Cells Tsai, Eing-Mei Wang, Yu-Chih Lee, Tony Tung-Yin Tsai, Cheng-Fang Chen, Hung-Sheng Lai, Feng-Jie Yokoyama, Kazunari K. Hsieh, Tsung-Hsun Wu, Ruey-Meei Lee, Jau-nan PLoS One Research Article Understanding the mechanisms in the generation of neural stem cells from pluripotent stem cells is a fundamental step towards successful management of neurodegenerative diseases in translational medicine. Albeit all-trans retinoic acid (RA) has been associated with axon outgrowth and nerve regeneration, the maintenance of differentiated neurons, the association with degenerative disease like Parkinson's disease, and its regulatory molecular mechanism from pluripotent stem cells to neural stem cells remain fragmented. We have previously reported that RA is capable of differentiation of human trophoblast stem cells to dopamine (DA) committed progenitor cells. Intracranial implantation of such neural progenitor cells into the 6-OHDA-lesioned substantia nigra pars compacta successfully regenerates dopaminergic neurons and integrity of the nigrostriatal pathway, ameliorating the behavioral deficits in the Parkinson’s disease rat model. Here, we demonstrated a dynamic molecular network in systematic analysis by addressing spatiotemporal molecular expression, intracellular protein-protein interaction and inhibition, imaging study, and genetic expression to explore the regulatory mechanisms of RA induction in the differentiation of human trophoblast stem cells to DA committed progenitor cells. We focused on the tyrosine receptor kinase (Trk), G proteins, canonical Wnt2B/β-catenin, genomic and non-genomic RA signaling transductions with Tyrosine hydroxylase (TH) gene expression as the differentiation endpoint. We found that at the early stage, integration of TrkA and G protein signalings aims for axonogenesis and morphogenesis, involving the novel RXRα/Gα(q/11) and RARβ/Gβ signaling pathways. While at the later stage, five distinct signaling pathways together with epigenetic histone modifications emerged to regulate expression of TH, a precursor of dopamine. RA induction generated DA committed progenitor cells in one day. Our results provided substantial mechanistic evidence that human trophoblast stem cell-derived neural stem cells can potentially be used for neurobiological study, drug discovery, and as an alternative source of cell-based therapy in neurodegenerative diseases like Parkinson’s disease. Public Library of Science 2015-11-25 /pmc/articles/PMC4659658/ /pubmed/26606046 http://dx.doi.org/10.1371/journal.pone.0143852 Text en © 2015 Tsai et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Tsai, Eing-Mei
Wang, Yu-Chih
Lee, Tony Tung-Yin
Tsai, Cheng-Fang
Chen, Hung-Sheng
Lai, Feng-Jie
Yokoyama, Kazunari K.
Hsieh, Tsung-Hsun
Wu, Ruey-Meei
Lee, Jau-nan
Dynamic Trk and G Protein Signalings Regulate Dopaminergic Neurodifferentiation in Human Trophoblast Stem Cells
title Dynamic Trk and G Protein Signalings Regulate Dopaminergic Neurodifferentiation in Human Trophoblast Stem Cells
title_full Dynamic Trk and G Protein Signalings Regulate Dopaminergic Neurodifferentiation in Human Trophoblast Stem Cells
title_fullStr Dynamic Trk and G Protein Signalings Regulate Dopaminergic Neurodifferentiation in Human Trophoblast Stem Cells
title_full_unstemmed Dynamic Trk and G Protein Signalings Regulate Dopaminergic Neurodifferentiation in Human Trophoblast Stem Cells
title_short Dynamic Trk and G Protein Signalings Regulate Dopaminergic Neurodifferentiation in Human Trophoblast Stem Cells
title_sort dynamic trk and g protein signalings regulate dopaminergic neurodifferentiation in human trophoblast stem cells
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4659658/
https://www.ncbi.nlm.nih.gov/pubmed/26606046
http://dx.doi.org/10.1371/journal.pone.0143852
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