The differentiation potential of human foetal neuronal progenitor cells in vitro

被引:49
作者
Riaz, SS
Theofilopoulos, S
Jauniaux, E
Stern, GM
Bradford, HF
机构
[1] Univ London Imperial Coll Sci Technol & Med, Dept Biol Sci, London SW7 2AZ, England
[2] Univ Coll Hosp, Dept Obstet & Gynaecol, London WC1E 6HX, England
来源
DEVELOPMENTAL BRAIN RESEARCH | 2004年 / 153卷 / 01期
关键词
human neural progenitor cells; dopaminergic neuron; serotonergic neuron; Parkinson's disease; BDNF; dopainine; forskolin; retinoic acid; GDNF; IL-1; beta; ventral mesencephalon;
D O I
10.1016/j.devbrainres.2004.07.006
中图分类号
Q [生物科学];
学科分类号
07 ; 0710 ; 09 ;
摘要
Previously, this laboratory has shown that human foetal progenitor cells derived from ventral mesencephalon (VM) can be developmentally directed towards a dopaminergic lineage. In the present study, the effects are reported of several as yet untested differentiation/survival factors on the controlled conversion of neural progenitor cells to dopaminergic neurons. Positive immunoreactivity to tyrosine hydroxylase (TH) and raised levels of dopamine (DA) and its metabolite, 3,4-dihydroxyphenylacetic acid (DOPAC), secreted into culture medium, were used to indicate the presence of the dopaminergic neuronal phenotype, i.e., active TH. Incubation with retinoic acid (RA) (0.5 muM) lead to an increase in the number of cultured cells showing positive immunocreactivity for the neuronal marker, microtubule-associated protein (MAP)-2ab. A concomitant increase in TH-positive immunoreactivity was also demonstrated. The brain-derived neurotrophic factor (BDNF) (50 ng/ml), glial-derived neurotrophic factor (GDNF) (10 ng/ml) and interleukin-1beta (IL-1beta) (10 ng/ml) also had positive effects in promoting neural progenitor cell differentiation towards the dopaminergic phenotype in the presence of dopamine (10 muM) and forskolin (Fsk) (10 muM). There was no synergy in this effect when progenitor cells were incubated with all of these agents simultaneously. The trans-differentiation potential of the progenitor cells to be directed towards other neurotransmitter phenotypic lineages was also investigated. It was found that, with the right cocktails of agents, serotonin (Set) (75 muM), acidic fibroblast growth factor (aFGF) (10 ng/ml), BDNF (50 ng/ml) and forskolin (10 muM), these same cells could be directed down the serotonergic cell lineage pathway (as judged by the appearance of tryptophan hydroxylase (TPH) positive immunoreactivity, and synthesis of 5-HT and its metabolites, secreted into the culture medium). However, no cocktail containing noradrenaline(10 nM - 500 muM), BDNF (50 ng/ml) and forskolin (10 muM) was found which promoted differentiation towards the noradrenergic cell phenotype as judged by the absence of any TH or DbetaH positive immunoreactivity, and no formation of 3,4-dihydroxyphenylethyleneglycol (DOPEG), the principal metabolite of noradrenaline. The controlled trans-differentiation potential of these cell could pave the way for development and harvesting of large numbers of neurons of the appropriate neurotransmitter phenotype for future transplantation therapies for the treatment of neurodegenerative diseases such as Parkinson's disease (PD) and Alzheimer's disease. (C) 2004 Published by Elsevier B.V.
引用
收藏
页码:39 / 51
页数:13
相关论文
共 52 条
[1]   THE HUMAN TRYPTOPHAN-HYDROXYLASE GENE - AN UNUSUAL SPLICING COMPLEXITY IN THE 5'-UNTRANSLATED REGION [J].
BOULARAND, S ;
DARMON, MC ;
MALLET, J .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1995, 270 (08) :3748-3756
[2]  
BOUVIER MM, 1995, J NEUROSCI, V15, P7141
[3]  
Brundin P, 1988, Brain Res, V467, P233
[4]   Host-guided migration allows targeted introduction of neurons into the embryonic brain [J].
Brustle, O ;
Maskos, U ;
McKay, RDG .
NEURON, 1995, 15 (06) :1275-1285
[5]   Regional incorporation and site-specific differentiation of striatal precursors transplanted to the embryonic forebrain ventricle [J].
Campbell, K ;
Olsson, M ;
Bjorklund, A .
NEURON, 1995, 15 (06) :1259-1273
[6]  
Chambon Pierre, 1994, Seminars in Cell Biology, V5, P115, DOI 10.1006/scel.1994.1015
[7]   Dopaminergic neurons protected from degeneration by GDNF gene therapy [J].
ChoiLundberg, DL ;
Lin, Q ;
Chang, YN ;
Chiang, YL ;
Hay, CM ;
Mohajeri, H ;
Davidson, BL ;
Bohn, MC .
SCIENCE, 1997, 275 (5301) :838-841
[8]   Histological evidence of fetal pig neural cell survival after transplantation into a patient with Parkinson's disease [J].
Deacon, T ;
Schumacher, J ;
Dinsmore, J ;
Thomas, C ;
Palmer, P ;
Kott, S ;
Edge, A ;
Penney, D ;
Kassissieh, S ;
Dempsey, P ;
Isacson, O .
NATURE MEDICINE, 1997, 3 (03) :350-353
[9]  
DU XY, 1995, J NEUROSCI, V15, P5420
[10]  
ENGELE J, 1991, J NEUROSCI, V11, P3070