Gene expression profiling of ciliary neurotrophic factor-overexpressing rat striatal progenitor cells (ST14A) indicates improved stress response during the early stage of differentiation.
Neuronal progenitor cells delivering neurotrophic factors are a promising therapeutic tool for treatment of neurodegenerative diseases. Although several promising results have come from studies in different animal models, detailed knowledge of the action of neurotrophic factors in the CNS is still lacking. A clonally derived, immortalized rat striatal cell line (ST14A) expressing ciliary neurotrophic factor (CNTF) offers a stable and controlled background with which to analyze CNTF actions on the transcriptional level in CNS progenitor cells. To identify early transcriptional changes induced by CNTF expression, we transfected the CNTF gene into ST14A cells, which differentiate at the nonpermissive temperature of 39 degrees C via suppression of the immortalizing SV40 large T antigen. This shows a CNTF-dependent hypoxic/ischemic stress response during the earliest stage of differentiation, with expression of specific transcripts and evidence of translational repression leading to decreased protein synthesis in the transfected cells. This process is mediated by the Ras/MAP kinase pathway and is accompanied by impaired proliferation and metabolism as well as signs of neuronal differentiation. The stress-like response in the early stage of differentiation improves the ability of the transfected cells to respond to and cope with a stressful environment in vivo. The present data indicate higher viability, longer life, and greater differentiation capacity of CNTF-ST14A cells if they are used for transplantation. We conclude that the stress-like response during the early stage of differentiation improves the ability of the CNTF-ST14A cells to respond and adapt to a stressful environment, which renders them useful candidate cells for in vivo trials of treatment for neurodegenerative diseases in animal models, e.g., of Huntington's disease.
Böttcher
Tobias
T
Department of Neurology, University of Rostock, Rostock, Germany.
Mix
Eilhard
E
Koczan
Dirk
D
Bauer
Peter
P
Pahnke
Jens
J
Peters
Sabine
S
Weinelt
Sabine
S
Knoblich
Rupert
R
Strauss
Ulf
U
Cattaneo
Elena
E
Thiesen
Hans-Jürgen
HJ
Rolfs
Arndt
A
D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D002460:Cell Line; D020934:Ciliary Neurotrophic Factor / Q000235:genetics* / Q000494:pharmacology; D003342:Corpus Striatum / Q000166:cytology*; D015870:Gene Expression / Q000187:drug effects / Q000502:physiology; D020869:Gene Expression Profiling; D018869:Heat-Shock Response / Q000235:genetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020801:Receptor, Ciliary Neurotrophic Factor / Q000235:genetics; D013234:Stem Cells / Q000166:cytology / Q000502:physiology*; D013696:Temperature
D020934:Ciliary Neurotrophic Factor; D020801:Receptor, Ciliary Neurotrophic Factor