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BDNF gene transfer to the mammalian brain using CNS-derived neural precursors

Rubio, F. T. ; Kokaia, Z. LU orcid ; Del Arco, A. ; García-Simón, M. I. ; Snyder, E. Y. ; Lindvall, O. LU ; Satrústegui, J. and Martínez-Serrano, A. (1999) In Gene Therapy 6(11). p.1851-1866
Abstract

Neural stem cell lines represent a homogeneous source of cells for genetic, developmental, and gene transfer and repair studies in the nervous system. Since both gene transfer of neurotrophic factors and cell replacement strategies are of immediate interest for therapeutical purposes, we have generated BDNF-secreting neural stem cell lines and investigated to what extent different endogenous levels of BDNF expression affect in vitro survival, proliferation and differentiation of these cells. Also we have investigated the in vivo effects of such BDNF gene transfer procedure in the rat neostriatum. Hippocampus- and cerebellum-derived cell lines reacted differently to manipulations aimed at varying their levels of BDNF production.... (More)

Neural stem cell lines represent a homogeneous source of cells for genetic, developmental, and gene transfer and repair studies in the nervous system. Since both gene transfer of neurotrophic factors and cell replacement strategies are of immediate interest for therapeutical purposes, we have generated BDNF-secreting neural stem cell lines and investigated to what extent different endogenous levels of BDNF expression affect in vitro survival, proliferation and differentiation of these cells. Also we have investigated the in vivo effects of such BDNF gene transfer procedure in the rat neostriatum. Hippocampus- and cerebellum-derived cell lines reacted differently to manipulations aimed at varying their levels of BDNF production. Overexpression of BDNF enhanced survival of both cell types, in a serum-deprivation assay. Conversely, and ruling out unspecific effects, expression of an antisense version of BDNF resulted in compromised survival of cerebellum-derived cells, and in a lethal phenotype in hippocampal progenitors. These data indicate that endogenous BDNF level strongly influences the in vitro survival of these cells. These effects are more pronounced for hippocampus- than for cerebellum-derived progenitors. Hippocampus-derived BDNF overproducers showed no major change in their capacity to differentiate towards a neuronal phenotype in vitro. In contrast cerebellar progenitors overproducing BDNF did not differentiate into neurons, whereas cells expressing the antisense BDNF construct generated cells with morphological features of neurons and expressing immunological neuronal markers. Taken together these results provide evidence that BDNF controls both the in vitro survival and differentiation of neural stem cells. After in vivo transplantation of BDNF-overproducing cells to the rat neostriatum, these survived better than the control ones, and induced the expected neurotrophic effects on cholinergic neurons. However, long-term (3 months) administration of BDNF resulted in detrimental effects, at this location. These findings may be of importance for the understanding of brain development, for the design of therapeutic neuro-regenerative strategies, and for cell replacement and gene therapy studies.

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author
; ; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Brain repair, Development, Gene therapy, Gene transfer, Neurotrophin, Transplantation
in
Gene Therapy
volume
6
issue
11
pages
16 pages
publisher
Nature Publishing Group
external identifiers
  • scopus:0032711822
  • pmid:10602381
ISSN
0969-7128
DOI
10.1038/sj.gt.3301028
language
English
LU publication?
yes
id
da501e62-6729-41de-a6b3-51c69dce7e37
date added to LUP
2019-09-03 17:03:03
date last changed
2024-01-01 18:44:23
@article{da501e62-6729-41de-a6b3-51c69dce7e37,
  abstract     = {{<p>Neural stem cell lines represent a homogeneous source of cells for genetic, developmental, and gene transfer and repair studies in the nervous system. Since both gene transfer of neurotrophic factors and cell replacement strategies are of immediate interest for therapeutical purposes, we have generated BDNF-secreting neural stem cell lines and investigated to what extent different endogenous levels of BDNF expression affect in vitro survival, proliferation and differentiation of these cells. Also we have investigated the in vivo effects of such BDNF gene transfer procedure in the rat neostriatum. Hippocampus- and cerebellum-derived cell lines reacted differently to manipulations aimed at varying their levels of BDNF production. Overexpression of BDNF enhanced survival of both cell types, in a serum-deprivation assay. Conversely, and ruling out unspecific effects, expression of an antisense version of BDNF resulted in compromised survival of cerebellum-derived cells, and in a lethal phenotype in hippocampal progenitors. These data indicate that endogenous BDNF level strongly influences the in vitro survival of these cells. These effects are more pronounced for hippocampus- than for cerebellum-derived progenitors. Hippocampus-derived BDNF overproducers showed no major change in their capacity to differentiate towards a neuronal phenotype in vitro. In contrast cerebellar progenitors overproducing BDNF did not differentiate into neurons, whereas cells expressing the antisense BDNF construct generated cells with morphological features of neurons and expressing immunological neuronal markers. Taken together these results provide evidence that BDNF controls both the in vitro survival and differentiation of neural stem cells. After in vivo transplantation of BDNF-overproducing cells to the rat neostriatum, these survived better than the control ones, and induced the expected neurotrophic effects on cholinergic neurons. However, long-term (3 months) administration of BDNF resulted in detrimental effects, at this location. These findings may be of importance for the understanding of brain development, for the design of therapeutic neuro-regenerative strategies, and for cell replacement and gene therapy studies.</p>}},
  author       = {{Rubio, F. T. and Kokaia, Z. and Del Arco, A. and García-Simón, M. I. and Snyder, E. Y. and Lindvall, O. and Satrústegui, J. and Martínez-Serrano, A.}},
  issn         = {{0969-7128}},
  keywords     = {{Brain repair; Development; Gene therapy; Gene transfer; Neurotrophin; Transplantation}},
  language     = {{eng}},
  month        = {{01}},
  number       = {{11}},
  pages        = {{1851--1866}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Gene Therapy}},
  title        = {{BDNF gene transfer to the mammalian brain using CNS-derived neural precursors}},
  url          = {{http://dx.doi.org/10.1038/sj.gt.3301028}},
  doi          = {{10.1038/sj.gt.3301028}},
  volume       = {{6}},
  year         = {{1999}},
}