Showing papers by "Clive N. Svendsen published in 2006"

Human neural progenitors deliver glial cell line-derived neurotrophic factor to parkinsonian rodents and aged primates.

Abstract: Glial cell line-derived neurotrophic factor (GDNF) has been shown to increase the survival and functioning of dopamine neurons in a variety of animal models and some recent human trials. However, delivery of any protein to the brain remains a challenge due to the blood/brain barrier. Here we show that human neural progenitor cells (hNPC) can be genetically modified to release glycosylated GDNF in vitro under an inducible promoter system. hNPC-GDNF were transplanted into the striatum of rats 10 days following a partial lesion of the dopamine system. At 2 weeks following transplantation, the cells had migrated within the striatum and were releasing physiologically relevant levels of GDNF. This was sufficient to increase host dopamine neuron survival and fiber outgrowth. At 5 weeks following grafting there was a strong trend towards functional improvement in transplanted animals and at 8 weeks the cells had migrated to fill most of the striatum and continued to release GDNF with transport to the substantia nigra. These cells could also survive and release GDNF 3 months following transplantation into the aged monkey brain. No tumors were found in any animal. hNPC can be genetically modified, and thereby represent a safe and powerful option for delivering growth factors to specific targets within the central nervous system for diseases such as Parkinson's.

Crossroads in GDNF therapy for Parkinson's disease.

Abstract: The development of a neuroprotective or neuroregenerative therapy for Parkinson's disease (PD) would be a major therapeutic advance. Unfortunately, results from a recent controlled clinical study delivering the neurotrophic factor, glial-derived neurotrophic factor (GDNF), directly into brain did not demonstrate efficacy and safety of such a treatment. A critical review of available data suggests that there are questions that need to be answered before the future of GDNF as a therapy for PD can be determined. © 2006 Movement Disorder Society

Glutamate enhances proliferation and neurogenesis in human neural progenitor cell cultures derived from the fetal cortex.

Abstract: Excitatory amino acids such as glutamate play important roles in the central nervous system We previously demonstrated that a neurosteroid, dehydroepiandrosterone (DHEA), has powerful effects on the cell proliferation of human neural progenitor cells (hNPC) derived from the fetal cortex, and this effect is modulated through NMDA receptor signaling Here, we show that glutamate can significantly increase the proliferation rates of hNPC The increased proliferation could be blocked by specific NMDA receptor antagonists, but not other glutamate antagonists for kainate-AMPA or metabotropic receptors The NR1 subunit of the NMDA receptor was detectable in elongated bipolar or unipolar cells with small cell bodies These NR1-positive cells were colocalized with GFAP immunoreactivity Detection of the phosphorylation of cAMP response element-binding protein (pCREB) revealed that a subset of NR1-positive hNPC could respond to glutamate Furthermore, we hypothesized that glutamate treatment may affect mainly the hNPC with a radial morphology and found that glutamate as well as DHEA selectively affected elongated hNPC; these elongated cells may be a type of radial glial cell Finally we asked whether the glutamate-responsive hNPC had an increased potential for neurogenesis and found that glutamate-treated hNPC produced significantly more neurons following differentiation Together these data suggest that glutamate stimulates the division of human progenitor cells with neurogenic potential

Massively parallel signature sequencing profiling of fetal human neural precursor cells.

Abstract: We have examined gene expression in multipotent neural precursor cells (NPCs) derived from human fetal (f) brain tissue and compared its expression profiles with embryonic stem (ESC) cells, embryoid body cell (EBC), and astrocyte precursors using the technique of massively parallel signature sequencing (MPSS). Gene expression profiles show that fNPCs express core neural stem cells markers and share expression profiles with astrocyte precursor cells (APCs) rather than ESC or EBC. Gene expression analysis shows that fNPCs differ from other adult stem and progenitor cells in their marker expression and activation of specific functional networks such as the transforming growth factorβ (TGFβ) and Notch signaling pathways. In addition, our results allow us to identify novel genes expressed in fNPCs and provide a detailed profile of fNPCs.

Genetically modified cells as a source for grafting in Parkinson's disease

Abstract: Parkinson’s disease (PD) is the second most common neurodegenerative disease and affects almost 1% of the population above the age of 50. PD was first described by James Parkinson in 1817. His essay on the “Shaking Palsy” reported the major symptoms of the disease, such as bradykinesia, resting tremor, and muscular rigidity (Parkinson, 2002). Most patients exhibit vegetative disturbances, with up to a third showing significant cognitive dysfunction (Lang and Lozano, 1998a,b), and almost 40% of PD patients are affected by depression (Oertel et al., 2001). The most conspicuous neuropathologic finding in PD is the progressive loss of dopamine (DA) neurons in the substantia nigra pars compacta (SNc). In the mammalian ventral midbrain, DA neurons can be found in three different regions, the SNc, the ventral tegmental area (VTA), and the retrorubral field. DA neurons of the VTA project to the ventromedial striatum and cortical area and form the mesolimbic pathway, which is involved in emotional behavior and motivation. DA neurons in the SNc project to the dorsolateral striatum and release DA, an important neurotransmitter which controls movement. Thus, the loss of DA neurons of the SNc leads to a reduction of striatal DA levels (Agid, 1991), that is responsible for some of the cardinal symptoms of Parkinson’s disease. Currently, there is no treatment that can prevent or retard progression of the disease. Since the late 1960s, the main approach to treating PD has been the pharmacological alleviation of the symptoms caused by the striatal

Neural Stem Cells

Abstract: Neural stem cells (NSCs) may teach us about how cell fate choices are made and which genes regulate these choices. In addition, NSCs might be a source of tissue for cell therapy. Studies focusing on the mechanisms of NSC growth and differentiation suggest they may be more plastic than had been anticipated. Keywords: stem cell; progenitor cell; embryonic stem cell; transplantation; ex vivo gene therapy