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ASN NEURO (2009) 1(2):art:e00009.doi:10.1042/AN20090002

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

Dhivyaa Alagappan*, Deborah A Lazzarino*, Ryan J Felling*, Murugabaskar Balan†, Sergei V Kotenko† and Steven W Levison*¹

^*Department of Neurology and Neuroscience, UMDNJ-New Jersey Medical School, Newark, NJ 07103, U.S.A.
^†Department of Biochemistry and Molecular Biology, UMDNJ-New Jersey Medical School, Newark, NJ 07103, U.S.A.

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.

Key words: brain injury, epidermal growth factor receptor (EGFR), neural stem cell, neurosphere, subventricular zone

Abbreviations: a.u., arbitrary units, BrdU, bromodeoxyuridine, CCA, common carotid artery, CNS, central nervous system, DAPI, 4′,6-diamidino-2-phenylindole, DIV, days in vitro, EGF, epidermal growth factor, EGFP, enhanced green fluorescent protein, EGFR, EGF receptor, FGF, fibroblast growth factor, FGFR, FGF receptor, GFP, green fluorescent protein, H/I, hypoxia/ischaemia, HRP, horseradish peroxidase, IRES, internal ribosome entry site, NG2, neuro-glial protein 2, NSP, neural stem progenitor, P6 etc. postnatal day 6 etc,, PSA-NCAM, poly-sialated neural cell adhesion molecule, SSEA-1, stage-specific embryonic antigen-1, SVZ, subventricular zone, TCA, trichloroacetic acid, TGF-α, tranforming growth factor-α

¹To whom correspondence should be addressed (email steve.levison@umdnj.edu).

Received 20 January 2009/13 April 2009; accepted 17 April 2009

Published as ASN NEURO Immediate Publication 17 April 2009, doi:10.1042/AN20090002

©2009 The Author(s) This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial Licence (http://creativecommons.org/licenses/by-nc/2.5/) which permits unrestricted non-commercial use, distribution and reproduction in any medium, provided the original work is properly cited.