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First published online May 22, 2008
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2007-0929v1
26/8/1973    most recent
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Submitted on November 5, 2007
Accepted on May 8, 2008

EMBRYONIC STEM CELLS

Tenascin-R Promotes Neuronal Differentiation of Embryonic Stem Cells and Recruitment of Host-derived Neural Precursor Cells after Excitotoxic Lesion of the Mouse Striatum

Gunnar Hargus 1, Yifang Cui 1, Janinne Sylvie Schmid 1, Jinchong Xu 1, Markus Glatzel 2, Melitta Schachner 3*, Christian Bernreuther 4

1 Zentrum für Molekulare Neurobiologie Hamburg; Universitätskrankenhaus Eppendorf, Universität Hamburg, Martinistr. 52, 20246 Hamburg, Germany
2 Institute for Neuropathology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany
3 Zentrum für Molekulare Neurobiologie Hamburg; Universitätskrankenhaus Eppendorf, Universität Hamburg, Martinistr. 52, 20246 Hamburg, Germany; W. M. Keck Center for Collaborative Neuroscience and Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, 604 Allison Road, New Jersey 08854, USA
4 Zentrum für Molekulare Neurobiologie Hamburg; Universitätskrankenhaus Eppendorf, Universität Hamburg, Martinistr. 52, 20246 Hamburg, Germany; Institute for Neuropathology, University Medical Center Hamburg Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany

* To whom correspondence should be addressed. E-mail: schachner{at}zmnh.uni-hamburg.de.

Correspondence may also be addressed to Christian Bernreuther at christian.bernreuther@uke.uni-hamburg.de.


  Abstract

Loss of GABAergic projection neurons under excitotoxic conditions in the striatum is associated with a disturbance of motor and cognitive functions as seen, for instance, in Huntington's disease. Since current treatments cannot replace degenerated neurons, research on alternative therapeutic approaches needs to be pursued. In this context, the transplantation of genetically modified stem cells into lesioned brain areas of patients is a possible alternative. In this study, green fluorescent protein (GFP)-labeled murine embryonic stem cells (ESCs) were stably transfected to overexpress the extracellular matrix molecule tenascin-R (TNR) which is expressed by striatal GABAergic neurons. TNR overexpressing ESCs were analyzed in comparison to their parental cells regarding neural differentiation and migration in vitro, and after transplantation into the striatum of quinolinic acid (QA)-treated mice which serve as a model for Huntington's disease. In comparison to sham-transfected control cells, TNR overexpressing ESCs showed enhanced differentiation into neurons in vitro, reduced migration in vitro and in vivo, and increased generation of GABAergic neurons and decreased numbers of astrocytes one month and two months after transplantation, but without significant effects on locomotor functions. Interestingly, TNR overexpressing ESCs transplanted into the striatum attracted host-derived neuroblasts from the rostral migratory stream and promoted stem cell-mediated recruitment of host-derived newborn neurons within the grafted area. Thus, we show for the first time that overexpression of an extracellular matrix molecule by in vitro pre-differentiated ESCs exerts beneficial effects on tissue regeneration in a mouse model of neurodegenerative disease.

______________________________________________________________________________

Author Contributions: G.H.: conception and design, provision of study material, collection of data, data analysis and interpretation, manuscript writing, final approval of manuscript; Y.C.: collection of data, provision of study material, final approval of manuscript; J.S.S.: collection of data, final approval of manuscript; J.X.: collection of data, final approval of manuscript; M.G.: data analysis and interpretation, final approval of manuscript; M.S.: conception and design, data analysis and interpretation, manuscript writing, financial support, administrative support, final approval of manuscript; C.B.: conception and design, provision of study material, collection of data, data analysis and interpretation, manuscript writing, administrative support, final approval of manuscript

 Key Words. Tenascin-R, embryonic stem cells, neuronal differentiation, quinolinic acid, mouse striatum, GABAergic projection neurons




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