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Neurospheres modified to produce glial cell line‐derived neurotrophic factor increase the survival of transplanted dopamine neurons
Author(s) -
Ostenfeld Thor,
Tai YuTzu,
Martin Peter,
Déglon Nicole,
Aebischer Patrick,
Svendsen Clive N.
Publication year - 2002
Publication title -
journal of neuroscience research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.72
H-Index - 160
eISSN - 1097-4547
pISSN - 0360-4012
DOI - 10.1002/jnr.10396
Subject(s) - glial cell line derived neurotrophic factor , neurotrophic factors , dopamine , neuroscience , brain derived neurotrophic factor , neurosphere , gdnf family of ligands , line (geometry) , neurotrophin , ciliary neurotrophic factor , biology , medicine , cellular differentiation , genetics , gene , adult stem cell , geometry , mathematics , receptor
Glial cell line‐derived neurotrophic factor (GDNF) has been shown to increase the survival of dopamine neurons in a variety of in vitro and in vivo model systems. Therefore, it constitutes an important therapeutic protein with the potential to ameliorate dopamine neuronal degeneration in Parkinson's disease or to support dopamine neuronal replacement strategies. However, biophysical and practical considerations present obstacles for the direct delivery of the GDNF protein to CNS neurons. Here we show that rodent neural precursor cells isolated and expanded in culture as neurospheres (NS) can be genetically modified to express green fluorescent protein (GFP) or to release GDNF using lentiviral constructs. GDNF‐NS increased the fibre outgrowth of primary embryonic dopamine neurons in cocultures, showing that the protein was released in biologically significant quantities. Furthermore, after transplantation into the 6‐hydroxydopamine‐lesioned rat striatum, GDNF‐NS significantly increased the survival of cografted primary dopamine neurons. However, this was not reflected in behavioural recovery in these animals. We found that, by 6 weeks, few cells expressed GDNF or GFP, suggesting either that transgene expression was down‐regulated over time or that the cells died. This may explain the initial effects on dopamine neuronal survival within the graft but the lack of long‐term effect on subsequent fibre outgrowth and behaviour. Providing sustained levels of neural precursor‐mediated transgene expression can be achieved following transplantation in the future; this approach may prove beneficial as an alternative therapeutic strategy in the cell‐based management of Parkinson's disease. © 2002 Wiley‐Liss, Inc.