Svendsen Laboratory
Clive Svendsen, PhD
Brain Development
So much is yet unknown about how the brain develops. By isolating and studying neural stem cells in the culture dish, we can examine the steps these cells take to become the mature cells of the brain. We can grow human neural stem cells for long periods of time and can direct them to form nerve cells as well as glia, or supporting cells of the brain.
We also use this culture system to model brain development in developmental disabilities such as Down Syndrome and Fragile X. In both of these syndromes, mistakes in brain development lead to mental retardation. For example, by comparing the development of control neural stem cells to those that carry Trisomy 21, we can learn about what may be different in brain development in Down Syndrome and learn more about brain development in general.
Neural stem cells are also being genetically engineered to carry genetic mutations that cause neurodegenerative diseases, such as Huntington's Disease and ALS (Amyotrophic Lateral Sclerosis). We can then study the behavior of these neural stem cells to discover why these cells die during disease.
Application to Neurodegenerative Diseases
Our research is focused on the hope that neural stem cells can be used to restore function in neurodegenerative diseases such as Parkinson's Disease, Huntington's Disease and Amyotrophic Lateral Sclerosis (ALS, Lou Gehrig's Disease). We are currently using a two-pronged approach to this end. First, we are assessing the ability of neural stem cells to replace dying nerve cells in these diseases. Second, we are genetically engineering neural stem cells to produce a drug (GDNF, glial derived neurotrophic factor) that can protect dying neurons. The neural stem cells can be transplanted into the brain and act as a drug pump to protect diseased nerve cells.
Research goals and interests:
How the central nervous system develops from a sheet of neuroepithelial cells remains a mystery. By isolating neural stem cells in vitro, we now have a model system for examining the factors important to both proliferation and lineage determination, which were previously impossible to contemplate for human tissues. Using a newly established culture system, we can grow human neural stem cells for long periods of time with exponential growth patterns. Upon removal of mitogens these cells differentiate into neurons and glia. Our immediate goals are to further understand this process at the cellular level using molecular and biochemical methods including FACS, gene manipulation and neural transplantation. Of particular interest are factors affecting proliferation (telomerase and cytokines), and subsequent factors affecting the differentiation of neurons, astrocytes and oligodendrocytes. This is currently being addressed using a combination of in vitro cloning, gene array, and transplantation of human neural stem cells into the embryonic rat CNS to assess plasticity.Another focus is generating dopamine neurons from human stem cells. Here experiments are underway using growth factor and induction molecules in addition to newly discovered transcription factors such as Nurr1, which may instruct neurons to become dopaminergic. Collaborations with viral groups have established reliable techniques for inserting these genes into the human cells and assessing their function. On the applied side of the work, expanded human neural stem cells could one day replace primary tissues used in clinical transplant programmes. However, appropriate pre-clinical work must first be carried out, to show these cells can integrate and differentiate appropriately. To this end we are working with animal models of PD, HD, MS and stroke to assess the possible use of human neural stem cells to restore function in these diseases. Through a long-standing interest in the mechanisms of neuronal cell death and growth factors, part of the lab continues to work in this area - which also relates tot he survival of neural stem cells. We have recently shown that lactate, pyruvate, GDNF and mouse neural stem cells can prevent the death of primary dopaminergic neurons in culture and made use of a powerful assay based on CREB phosphorylation to asses growth factor responsiveness at the single cell level.
Relevant Publications:
Svendsen, C.N., Caldwell, M.A, Shen, J. ter Borg, M.G., Rosser, A.E., Tyers, P., Karmiol, S. and Dunnett, S.B. (1997) Long term survival of human central nervous system progenitor cell transplanted into a rat model of Parkinson's Disease. Experimental Neurology,148:135-146Ciccolini, F. and Svendsen, C.N. (1998) FGF-2 promotes acquisition of EGF responsiveness in mouse striatal precursor cells: Identification of neuronal precursor cells responding to both EGF and FGF-2. J. Neuroscience, 18: 7869-7880.
Svendsen, C.N. and Smith, A.G. (1999) New prospects for human stem cell therapy in the nervous system. Trends Neurosci. 22:357-364.
Ostenfeld, T., Caldwell, M.A., Prowse, K.R., Linskens, M.H., Jauniaux, E. and Svendsen, C.N. (2000) Human neural precursor cells express low levels of telomerase in vitro and show diminishing cell proliferation with extensive axonal outgrowth following transplantation. Experimental Neurology, 164: 215-226
Caldwell M. A., He X., Wilkie N., Pollack S., Marshall G., Wafford K. A., and Svendsen C. N. (2001) Growth factors regulate the survival and fate of cells derived from human neurospheres. Nat Biotechnol 19, 475-479.
Bahn S., Mimmack M., Ryan M., Caldwell M. A., Jauniaux E., Starkey M., Svendsen C. N., and Emson P. (2002) Neuronal target genes of the neuron-restrictive silencer factor in neurospheres derived from fetuses with Down's syndrome: a gene expression study. Lancet 359, 310-315.
Wu, P. , Ye, Y., Svendsen, C.N. (2002) Transduction of human neural progenitor cells using recombinant adeno-associated viruses. Gene Ther. 9, 245-255.
Ostenfeld T., Joly E., Tai Y. T., Peters A., Caldwell M., Jauniaux E., and Svendsen C. N. (2002) Regional specification of rodent and human neurospheres. Brain Res Dev Brain Res 134, 43-55.
Ostenfeld T., Tai Y. T., Martin P., Deglon N., Aebischer P., and Svendsen C. N. (2002) Neurospheres modified to produce glial cell line-derived neurotrophic factor increase the survival of transplanted dopamine neurons. Journal of Neuroscience Research 69, 955-965.
Gill, S. S., Patel, N. J., Hotton, G. R., O’Sullivan, K., McCarter, R., Bunnage, M., Brooks, D. J., Svendsen, C. N. and Heywood, P. (2003) Direct brain infusion of glial cell line-derived neurotrophic factor in Parkinson disease. Nature Medicine 69, 589-595
Wright, L.S., Li, J., Caldwell, M. A., Wallace, K., Johnson, J. A., and Svendsen, C. N. (2003) Gene expression in human neural stem cells: effects of leukemia inhibitory factor. J. Neurochem. 86, 179-195.
Behrstock S, Ebert A, McHugh J, Vosberg S, Moore J, Schneider B, Capowski E, Hei D, Kordower J, Aebischer P, Svendsen CN. (2006) Human neural progenitors deliver glial cell line-derived neurotrophic factor to parkinsonian rodents and aged primates. Gene Ther. 13:379-88.
Wright LS, Prowse KR, Wallace K, Linskens MHK, Svendsen CN. (2006) Human neural progenitor cells undergo natural senescence and decreased neurogenesis following extended expansion in culture. Experimental Cell Res. 312: 2107-20.
Nelson AD and Svendsen CN. (2006) Low concentrations of extracellular FGF-2 are sufficient but not essential for neurogenesis from human neural progenitor cells. Mol Cell Neurosci. 33:29-35
Kim HJ, Sugimori M, Nakafuku M, and Svendsen CN. (2007) Control of neurogenesis and tyrosine hydroxylase expression in neural progenitor cells through bHLH proteins and Nurr1. Exp Neurol. 203:394-405.
Schneider, B. L., Seehus, C.R., Capowski, E.E, Aebischer, P., Zhang, S.C. and Svendsen CN. Over-expression of alpha‑synuclein in progenitors generated from human fetal brain tissue and embryonic stem cells leads to specific changes in fate and differentiation. Human Molecular Genetics (in press)