Brain injury expands the numbers of neural stem cells and progenitors in the SVZ by enhancing their responsiveness to EGF

被引:48
作者
Alagappan, Dhivyaa [1 ]
Lazzarino, Deborah A. [1 ]
Felling, Ryan J. [1 ]
Balan, Murugabaskar [2 ]
Kotenko, Sergei V. [2 ]
Levison, Steven W. [1 ]
机构
[1] Univ Med & Dent New Jersey, New Jersey Med Sch, Dept Neurol & Neurosci, Newark, NJ 07103 USA
[2] Univ Med & Dent New Jersey, New Jersey Med Sch, Dept Biochem & Mol Biol, Newark, NJ 07103 USA
基金
美国国家卫生研究院;
关键词
brain injury; epidermal growth factor receptor (EGFR); neural stem cell; neurosphere; subventricular zone; EPIDERMAL-GROWTH-FACTOR; HYPOXIC-ISCHEMIC INJURY; CENTRAL-NERVOUS-SYSTEM; SUBVENTRICULAR ZONE; FACTOR RECEPTOR; KINASE INHIBITOR; PERINATAL BRAIN; FACTOR-ALPHA; ADULT BRAIN; TGF-ALPHA;
D O I
10.1042/AN20090002
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
There is an increase in the numbers of neural precursors in the SVZ (subventricular zone) after moderate ischaemic injuries, but the extent of stem cell expansion and the resultant cell regeneration is modest. Therefore our studies have focused on understanding the signals that regulate these processes towards achieving a more robust amplification of the stem/progenitor cell pool. The goal of the present study was to evaluate the role of the EGFR [EGF (epidermal growth factor) receptor] in the regenerative response of the neonatal SVZ to hypoxic/ischaemic injury. We show that injury recruits quiescent cells in the SVZ to proliferate, that they divide more rapidly and that there is increased EGFR expression on both putative stem cells and progenitors. With the amplification of the precursors in the SVZ after injury there is enhanced sensitivity to EGF, but not to FGF (fibroblast growth factor)-2. EGF-dependent SVZ precursor expansion, as measured using the neurosphere assay, is lost when the EGFR is pharmacologically inhibited, and forced expression of a constitutively active EGFR is sufficient to recapitulate the exaggerated proliferation of the neural stem/progenitors that is induced by hypoxic/ischaemic brain injury. Cumulatively, our results reveal that increased EGFR signalling precedes that increase in the abundance of the putative neural stem cells and our studies implicate the EGFR as a key regulator of the expansion of SVZ precursors in response to brain injury. Thus modulating EGFR signalling represents a potential target for therapies to enhance brain repair from endogenous neural precursors following hypoxic/ischaemic and other brain injuries.
引用
收藏
页码:95 / 111
页数:17
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