Heparin stabilizes FGF-2 and modulates striatal precursor cell behavior in response to EGF

被引:48
作者
Caldwell, MA
Garcion, E
terBorg, MG
He, XL
Svendsen, CN
机构
[1] Univ Cambridge, Ctr Brain Repair, Cambridge CB2 2PY, England
[2] Univ Wisconsin, Stem Cell Res Program, Waisman Ctr, Madison, WI 53705 USA
[3] Univ Wisconsin, Dept Anat & Neurol, Madison, WI 53705 USA
基金
英国惠康基金;
关键词
FGF-2; heparin; phospho-CREB; progenitor cell; neural stem cell; BrdU; EGF;
D O I
10.1016/j.expneurol.2004.05.007
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
Fibroblast and epidermal growth factors (FGF-2 and EGF) are powerful mitogens for neural precursor cells isolated from the developing striatum and grown as neurospheres. However, questions remain as to the exact role of each of these molecules, and how the proteoglycan heparin may modify their behavior. Here, we show that FGF-2 is remarkably unstable in culture media, but that heparin could completely prevent its degradation, which led to faster cell growth rates. In addition, heparin significantly increased the number of cells within the E14 striatum responding to a brief pulse of FGF-2. In contrast, EGF was unable to stimulate the growth of E14 striatal precursors. However, EGF could induce the division of E18 striatal precursors as neurospheres and acted synergistically with FGF-2. FGF-2/heparin neurospheres generated significantly more neurons than EGF neurospheres. Interestingly, the addition of heparin to EGF neurospheres, which had no effects on EGF stability or growth rates, increased the numbers of neurons generated to that seen for FGF-2/heparin neurospheres. EGF neurospheres were found to produce FGF-2, but addition of heparin did not affect its concentration within cells or in the medium suggesting this released FGF-2 may already be bound to a proteoglycan. In addition, expanding cells with EGF plus heparin in the presence of an FGF-2 blocker did not have a significant effect on the number of neurons generated confirming that the increase in neuronal number is through a mechanism which is independent of FGF-2. (C) 2004 Elsevier Inc. All rights reserved.
引用
收藏
页码:408 / 420
页数:13
相关论文
共 62 条
[51]   Heparan sulfate proteoglycans control intracellular processing of bFGF in vascular smooth muscle cells [J].
Sperinde, GV ;
Nugent, MA .
BIOCHEMISTRY, 1998, 37 (38) :13153-13164
[52]   Restricted growth potential of rat neural precursors as compared to mouse [J].
Svendsen, CN ;
Skepper, J ;
Rosser, AE ;
terBorg, MG ;
Tyres, P ;
Ryken, T .
DEVELOPMENTAL BRAIN RESEARCH, 1997, 99 (02) :253-258
[53]  
SVENDSEN CN, 1995, EXP BRAIN RES, V102, P407
[54]   Distinct neural stem cells proliferate in response to EGF and FGF in the developing mouse telencephalon [J].
Tropepe, V ;
Sibilia, M ;
Ciruna, BG ;
Rossant, T ;
Wagner, EF ;
van der Kooy, D .
DEVELOPMENTAL BIOLOGY, 1999, 208 (01) :166-188
[55]   Why stem cells? [J].
van der Kooy, D ;
Weiss, S .
SCIENCE, 2000, 287 (5457) :1439-1441
[56]   FUNCTIONS OF BASIC FIBROBLAST GROWTH-FACTOR AND NEUROTROPHINS IN THE DIFFERENTIATION OF HIPPOCAMPAL-NEURONS [J].
VICARIOABEJON, C ;
JOHE, KK ;
HAZEL, TG ;
COLLAZO, D ;
MCKAY, RDG .
NEURON, 1995, 15 (01) :105-114
[57]   Stimulation of neonatal and adult brain neurogenesis by subcutaneous injection of basic fibroblast growth factor [J].
Wagner, JP ;
Black, IB ;
DiCicco-Bloom, E .
JOURNAL OF NEUROSCIENCE, 1999, 19 (14) :6006-6016
[58]   Mitogen and substrate differentially affect the lineage restriction of adult rat subventricular zone neural precursor cell populations [J].
Whittemore, SR ;
Morassutti, DJ ;
Walters, WM ;
Liu, RH ;
Magnuson, DSK .
EXPERIMENTAL CELL RESEARCH, 1999, 252 (01) :75-95
[59]   Coupling of the RAS-MAPK pathway to gene activation by RSK2, a growth factor-regulated CREB kinase [J].
Xing, J ;
Ginty, DD ;
Greenberg, ME .
SCIENCE, 1996, 273 (5277) :959-963
[60]  
YANON A, 1991, CELL, V64, P841