Dynamic trk and G protein signalings regulate dopaminergic neurodifferentiation in human trophoblast stem cells
Journal
PLoS ONE
Journal Volume
10
Journal Issue
11
Pages
e0143852
Date Issued
2015
Author(s)
Abstract
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/Gαq/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. ? 2015 Tsai et al. 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 credited.
SDGs
Other Subjects
beta catenin; calcium calmodulin dependent protein kinase II; cyclic AMP dependent protein kinase; cyclic AMP responsive element binding protein; guanine nucleotide binding protein; guanine nucleotide binding protein alpha subunit; guanine nucleotide binding protein beta subunit; protein tyrosine kinase; protein tyrosine kinase A; retinoic acid; retinoic acid receptor alpha; retinoic acid receptor beta; unclassified drug; Wnt2 protein; Wnt2b protein; beta catenin; calcium calmodulin dependent protein kinase II; CREB1 protein, human; cyclic AMP responsive element binding protein; glycogen synthase kinase 3; guanine nucleotide binding protein; homeodomain protein; MAPT protein, human; multiprotein complex; nucleoporin; NUP214 protein, human; protein binding; protein kinase B; protein tyrosine kinase A; retinoic acid receptor; retinoic acid receptor beta; retinoid X receptor alpha; target of rapamycin kinase; tau protein; transcription factor; transcription factor Pitx3; tyrosine 3 monooxygenase; Article; calcium cell level; cell differentiation; cell growth; controlled study; dopaminergic system; enzyme inhibition; epigenetics; gene control; gene expression; genetic variability; histone modification; human; human cell; molecular imaging; nerve fiber growth; protein expression; protein function; protein protein interaction; regulatory mechanism; signal transduction; stem cell; trophoblast; animal; axon; biological model; calcium signaling; cell line; cytology; disease model; dopaminergic nerve cell; drug effects; gene expression regulation; genetics; metabolism; morphogenesis; Parkinson disease; protein transport; rat; stem cell; trophoblast; Animals; Axons; beta Catenin; Calcium Signaling; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Cell Differentiation; Cell Line; Cyclic AMP Response Element-Binding Protein; Disease Models, Animal; Dopaminergic Neurons; Gene Expression Regulation; Glycogen Synthase Kinase 3; GTP-Binding Proteins; Homeodomain Proteins; Humans; Models, Biological; Morphogenesis; Multiprotein Complexes; Nuclear Pore Complex Proteins; Parkinson Disease; Protein Binding; Protein Transport; Proto-Oncogene Proteins c-akt; Rats; Receptor, trkA; Receptors, Retinoic Acid; Retinoid X Receptor alpha; Signal Transduction; Stem Cells; tau Proteins; TOR Serine-Threonine Kinases; Transcription Factors; Trophoblasts; Tyrosine 3-Monooxygenase
Type
journal article