Clive N. Svendsen

 

 

Biology of Neural Stem Cells: Fate Choices In Vitro and Repair Following Transplantation

E-mail: svendsen@waisman.wisc.edu

Research Strengths: Development: Plasticity and Repair, Neurobiology of Disease

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, differential display 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 to the 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 assess growth factor responsiveness at the single cell level.

Lab Website:

http://www.waisman.wisc.edu/scrp/svendsen.html

Selected Publications:

• Caldwell, M.A., X. He, N. Wilkie, S. Pollack, G. Marshall, K. Wafford, and C.N. Svendsen. 2001. Growth factors regulate the survival and fate of cells derived from human neurosphere cultures. Nat. Biotechnol. 19: 475-479. [PDF]
• Ostenfeld, T., M.A. Caldwell, K.R. Prowse, M.H. Linskens, E. Jauniaux, and C.N. Svendsen. 2000. Human neural precursor cells express low levels of telomerase in vitro and show diminishing cell proliferation with extensive axonal outgrowth following transplantation. Exper. Neurol. 164: 215-226.
• Svendsen, C.N. and A.G. Smith. 1999. New prospects for human stem cell therapy in the nervous system. Trends Neurosci. 22: 357-364. [PDF]
• Ciccolini, F. and C.N Svendsen. 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. Neurosci. 18: 7869-7880. [PDF]
• Svendsen, C.N., M.A. Caldwell, J. Shen, M.G. ter Borg, A.E. Rosser, P. Tyers, S. Kermiol, and S.B Dunnett. 1997. Long term survival of human central nervous system progenitor cell transplanted into a rat model of Parkinson's Disease. Exper. Neurol. 148: 135-146.