Premium
Increase in dopaminergic neurons from mouse embryonic stem cell‐derived neural progenitor/stem cells is mediated by hypoxia inducible factor‐1α
Author(s) -
Kim TaeSun,
Misumi Sachiyo,
Jung ChaGyun,
Masuda Tadashi,
Isobe Yoshiaki,
Furuyama Fujiya,
Nishino Hitoo,
Hida Hideki
Publication year - 2008
Publication title -
journal of neuroscience research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.72
H-Index - 160
eISSN - 1097-4547
pISSN - 0360-4012
DOI - 10.1002/jnr.21687
Subject(s) - leukemia inhibitory factor , embryonic stem cell , neural stem cell , tyrosine hydroxylase , stem cell , neurotrophic factors , dopaminergic , biology , stem cell factor , progenitor cell , microbiology and biotechnology , glial cell line derived neurotrophic factor , hypoxia inducible factors , chemistry , dopamine , biochemistry , endocrinology , receptor , gene
A reliable method to induce neural progenitor/stem cells (NPCs) into dopaminergic (DAergic) neurons has not yet been established. As well, the mechanism involved remains to be elucidated. To induce DAergic differentiation from NPCs, a cytokine mixture (C‐Mix) of interleukin (IL)‐1β, IL‐11, leukemia‐inhibitory factor (LIF), and glial‐derived neurotrophic factor or low oxygen (3.5% O 2 : L‐Oxy) was used to treat embryonic stem (ES) cell‐derived NPCs. Treatment with C‐Mix increased the number of tyrosine hydroxylase (TH)‐positive cells compared with controls (2.20‐fold of control). The C‐Mix effect was induced by mainly LIF or IL‐1β treatment. Although L‐Oxy caused an increase in TH‐positive cells (1.34‐fold), the combination of L‐Oxy with C‐Mix did not show an additive effect. Increases in DA in the medium were shown in the presence of C‐Mix, LIF, and L‐Oxy by high‐performance liquid chromatography. Gene expression patterns of neural markers [tryptophan hydroxylase (TPH), GAD67, GluT1, β‐tubulin III, glial fibrillary acidc protein, and TH] were different in C‐Mix and L‐Oxy treatments. Because increases in hypoxia‐inducible factor (HIF)‐1α protein were found in both treatments, we investigated the effect of HIF‐1α on differentiation of NPCs to DAergic neurons. Inhibition of HIF‐1α by the application of antisense oligodeoxynucleotides (ODNs) to NPCs caused a decrease in TH‐positive cells induced by LIF treatment. Gene expressions of TH, GAD67, and GluT1 were decreased, and those of TPH, β‐tubulin III, and S‐100β were increased by treatment with just ODNs, indicating the importance of the endogenous effect of HIF‐1α on neuronal differentiation. These data suggest that enhanced differentiation into DAergic neurons from ES cell‐derived NPCs was induced by C‐Mix or L‐Oxy mediated by HIF‐1α. © 2008 Wiley‐Liss, Inc.