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J. Biol. Chem., Vol. 283, Issue 47, 32244-32253, November 21, 2008

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Hepatocyte Growth Factor/c-MET Axis-mediated Tropism of Cord Blood-derived Unrestricted Somatic Stem Cells for Neuronal Injury^*

Thorsten Trapp¹, Gesine Kögler, Abdelouahid El-Khattouti, Rüdiger V. Sorg, Michael Besselmann^¶, Melanie Föcking^||, Christian P. Bührle^**, Ingo Trompeter, Johannes C. Fischer, and Peter Wernet

From the Institute for Transplantation Diagnostics and Cell Therapeutics, Heinrich-Heine-University Medical Center, D-40225 Düsseldorf, Germany, the European Graduate School for Neuroscience and the ^¶Department of Neurology, University Medical Center Münster, D-48129 Münster, Germany, the ^||Department of Psychiatry, Education and Research Centre, Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin 2, Ireland, and the ^**Department of Stereotaxy and Functional Neurosurgery, University of Cologne, D-50924 Cologne, Germany

An under-agarose chemotaxis assay was used to investigate whether unrestricted somatic stem cells (USSC) that were recently characterized in human cord blood are attracted by neuronal injury in vitro. USSC migrated toward extracts of post-ischemic brain tissue of mice in which stroke had been induced. Moreover, apoptotic neurons secrete factors that strongly attracted USSC, whereas necrotic and healthy neurons did not. Investigating the expression of growth factors and chemokines in lesioned brain tissue and neurons and of their respective receptors in USSC revealed expression of hepatocyte growth factor (HGF) in post-ischemic brain and in apoptotic but not in necrotic neurons and of the HGF receptor c-MET in USSC. Neuronal lesion-triggered migration was observed in vitro and in vivo only when c-MET was expressed at a high level in USSC. Neutralization of the bioactivity of HGF with an antibody inhibited migration of USSC toward neuronal injury. This, together with the finding that human recombinant HGF attracts USSC, document that HGF signaling is necessary for the tropism of USSC for neuronal injury. Our data demonstrate that USSC have the capacity to migrate toward apoptotic neurons and injured brain. Together with their neural differentiation potential, this suggests a neuroregenerative potential of USSC. Moreover, we provide evidence for a hitherto unrecognized pivotal role of the HGF/c-MET axis in guiding stem cells toward brain injury, which may partly account for the capability of HGF to improve function in the diseased central nervous system.

Received for publication, February 1, 2008 , and in revised form, May 30, 2008.

^* This work was supported by European Community Grants BIO4-CT98-0293, QLG3-CT-2000-00934, and QLK6-CT-2000-60042 (to the Trapp laboratory). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Laboratory for Neuroregeneration & Neuroethics Group, ITZ, Heinrich-Heine-University Medical Center, Moorenstr. 5, Bldg. 14.80, D-40225 Düsseldorf, Germany. Tel.: 49-211-81-1-6924; E-mail: trapp{at}itz.uni-duesseldorf.de.

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