Isolation and Characterization of Stem Cells from the Adult Human Central Nervous System and Brain Tumours
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AbstractThe central nervous system (CNS) was viewed as a static organ incapable of neurogenesis. The discovery of adult human neural stem cells (AHNSCs) capable of self-renewal, proliferation and multipotent differentiation opens new opportunities for stem cell-based treatment of CNS disorders, either by stimulating neurogenesis in vivo or transplanting AHNSCs. The main challenges facing clinical application include the limited availability of AHNSCs and their ability to develop into functional neurons. Recently, cells similar to AHNSCs known as tumour stem cells (TSCs) have been isolated from brain tumours. The TSC model proposes that TSCs drive glioma initiation and maintenance. Targeting TSCs may prove effective in cancer therapy. Given their intimate relation, we have investigated AHNSCs and TSCs.
We isolated AHNSCs from the ventricular wall of patients undergoing surgery for refractory epilepsy or hydrocephalus. AHNSCs exhibited self-renewal and proliferated into neurospheres. Furthermore, they exhibited multipotent differentiation into neurons, astrocytes and oligodendrocytes. Using electrophysiology, we showed that after 4 weeks neurons developed functional activity; they exhibited mature action potentials and communicated using GABAergic and glutamatergic synapses. We also demonstrated that AHNSCs isolated from the terminal end of the spinal cord, can develop into functional neurons. The functional differentiation of AHNSCs holds promise for the treatment of neurodegenerative CNS disorders.
We isolated TSCs from patients undergoing resections for low grade and high grade gliomas and compared them to AHNSCs. Given their similarities, we demonstrated several key differences including uncontrolled proliferation, precocious differentiation and tumour generation upon transplantation in vivo. Utilizing such differences may lead to effective therapies targeting TSCs whilst sparing resident AHNSCs. This may have a profound effect on the dismal prognosis of gliomas.
List of papers
|PAPER I Development of neuronal networks from single stem cells harvested from the adult human brain. Moe MC, Westerlund U, Varghese M, Berg-Johnsen J, Svensson M, Langmoen IA. Neurosurgery. 2005 56:1182-8. The paper is not available in DUO. The published version is available at: http://dx.doi.org/10.1227/01.NEU.0000159881.09663.6D|
|PAPER II Multipotent progenitor cells from the adult human brain: neurophysiological differentiation to mature neurons. Moe MC, Varghese M, Danilov AI, Westerlund U, Ramm-Pettersen J, Brundin L, Svensson M, Berg-Johnsen J and Langmoen IA. Brain. 2005 128:2189-99. The paper is not available in DUO. The published version is available at: http://dx.doi.org/10.1093/brain/awh574|
|PAPER III Neural Progenitors from Adult Filum Terminale are plastic and can develop into functional neurons. Varghese M, Olstorn H, Berg-Johnsen J, Moe MC, Murrell W and Langmoen IA. Stem Cells and Development 2008 In press (electronic preprint available at Pub Med). The paper is not available in DUO.|
|PAPER IV A Comparison between Stem Cells from the Adult Human Brain and Brain Tumours. Varghese M, Olstorn H, Sandberg C, Vik-Mo EO, Noordhuis P, Nistér M, Berg-Johnsen J, Moe MC and Langmoen IA. Neurosurgery. 2008 Dec;63(6):1033-4; The paper is not available in DUO. The published version is available at: http://dx.doi.org/10.1227/01.NEU.0000335792.85142.B0|