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1. Previous and current research

Relative to most organs, the brain has very limited regenerative potential. But within it, a population of immature cells persists in adulthood, suggesting that it, too, possesses an innate ability to repair itself. These cells are termed neural stem cells and are considered immature because they have not fulfilled their developmental options; instead, they have maintained their ability to proliferate, and have kept open their options to mature into any one of the main cell types of the brain (neurons, astrocytes, or oligodendrocytes).

In mammals, adult neural stem cells were first discovered in two small areas of the rodent brain, the subventricular zone, and the dentate gyrus of the hippocampus. In these areas, neural stem cells are able to proliferate and some of the new cells mature to become neurons. This may be a mechanism to provide new neurons throughout the lifespan of the animal in areas that are involved with olfaction, learning, and memory [all experience-based processes with a need to register information].

But we recently showed that in the adult brain and spinal cord, neural stem cells are plentiful and widespread. We address the question of their function to understand how they can be coaxed to help in disease. To do so, we study the mechanisms that regulate stem cell survival and proliferation, and as a consequence, their numbers. We have discovered that these cells use biochemical pathways in distinct ways than most mature cell types in the body, and we have found pharmacological means to regulate their numbers. This has provided a tool to study their role in the context of neurodegenerative diseases such as Parkinson’s disease, and brain insults such as ischemic stroke.

We found that a variety of treatments that increase the numbers of these cells result in the dramatic rescue of neurons that would otherwise die due to disease. We think this is because neural stem cells physically associate with neurons and produce factors that support their survival. Our results show that great benefits can be achieved by targeting the endogenous population of neural stem cells, and encouraging them to protect injured neurons.
 

2. Future Prospects and goals

 
Our efforts are focused on uncovering additional facets of the signals that regulate neural stem cells in order to devise new treatments, including ones that can be used clinically. This requires basic research into the mechanisms that control stem cell survival and proliferation. Recently, we showed that cholera toxin, which regulates a number of cellular functions also regulates the biochemical pathways we previously discovered and greatly increases stem cell numbers in culture.

We are also interested to expand the scope of our work beyond the nervous system and into other organs, such as the pancreas, because we have shown that many of the core principles that regulate stem cells from the brain are shared by other tissues. This effort could lead to therapeutic strategies that aim to stop the degeneration of tissues and not merely treat symptoms.
A more comprehensive and technical description of our findings can be found following this link:

 
Stem Cell Biology Research - www.innaterepair.net

 

 3. Publications

 
Journal Articles:
 

1. Androutsellis-Theotokis, A., Walbridge, S., Park, D.M., Lonser, R.R. & McKay, R.D.G., Cholera toxin regulates a signaling pathway critical for the expansion of neural stem cell cultures from the fetal and adult rodent brains. PLoS ONE, 2010.
2. Androutsellis-Theotokis, A., Rueger, M.A. , Park, D.M., Boyd, J.D., Padmanabhan, R., Campanati, L., Stewart, C.V., LeFranc, Y., Plenz, D., Walbridge, S., Lonser, R.R. & McKay, R.D.G., Angiogenic Factors Stimulate Growth of Adult Neural Stem Cells, PLoS ONE, 2010.
3. Androutsellis-Theotokis, A., Rueger, M.A., Park, D.M., Mkhikian, H., Korb, E., Poser, S.W., Walbridge, S., Munasinghe, J., Koretsky, A.P., Lonser, R.R., McKay, R.G. (2009). Targeting neural precursors in the adult brain rescues injured dopamine neurons. Proc Natl Acad Sci U S A.
4. A. Androutsellis-Theotokis, M. A. Rueger, H. Mkhikian, E. Korb, R. D. McKay, (2008) Signaling pathways controlling neural stem cells slow progressive brain disease. Cold Spring Harb Symp Quant Biol.
5. Androutsellis-Theotokis, A., Leker, R. R., Soldner, F., Hoeppner, D. J., Ravin, R., Poser, S. W., Rueger, M. A., Bae, S. K., Kittappa, R. & McKay, R. D. (2006). Notch signalling regulates stem cell numbers in vitro and in vivo. Nature 442, 823-6.
6. Androutsellis-Theotokis, A., Goldberg, N. R., Ueda, K., Beppu, T., Beckman, M. L., Das, S., Javitch, J. A. & Rudnick, G. (2003). Characterization of a functional bacterial homologue of sodium-dependent neurotransmitter transporters. J Biol Chem 278, 12703-9.
7. Androutsellis-Theotokis, A. & Rudnick, G. (2002). Accessibility and conformational coupling in serotonin transporter predicted internal domains. J Neurosci 22, 8370-8.
8. Androutsellis-Theotokis, A., Ghassemi, F. & Rudnick, G. (2001). A conformationally sensitive residue on the cytoplasmic surface of serotonin transporter. J Biol Chem 276, 45933-8.
9. Androutsellis-Theotokis, A., McCormack, W. J., Bradford, H. F., Stern, G. M. & Pliego-Rivero, F. B. (1996). The depolarisation-induced release of [125I]BDNF from brain tissue. Brain Res 743, 40-8.
10. A. Soeda, M. Park, D. Lee, A. Mintz, A. Androutsellis-Theotokis, R.D.G. McKay, J. Engh, T. Iwama, T. Kunisada, A.B. Kassam, I.F. Pollack, and D.M. Park. Hypoxia promotes expansion of the CD133-positive glioma stem cells through activation of HIF-1á, Cancer Research, 2009.
11. Booth, W.B., Mack, L.D., Androutsellis-Theotokis, A., McKay, R.D., Boulanger, C.A., and Smith, G.H., (2008). The Mammary Microenvironment Alters the Differentiation Repertoire of Neural Stem Cells. PNAS.
12. Leker, R. R., Soldner, F., Velasco, I., Gavin, D. K., Androutsellis-Theotokis, A. & McKay, R. D. (2007). Long-lasting regeneration after ischemia in the cerebral cortex. Stroke 38, 153-61.
13. Sato, Y., Zhang, Y. W., Androutsellis-Theotokis, A. & Rudnick, G. (2004). Analysis of transmembrane domain 2 of rat serotonin transporter by cysteine scanning mutagenesis. J Biol Chem 279, 22926-33.
14. Ni, Y. G., Chen, J. G., Androutsellis-Theotokis, A., Huang, C. J., Moczydlowski, E. & Rudnick, G. (2001). A lithium-induced conformational change in serotonin transporter alters cocaine binding, ion conductance, and reactivity of Cys-109. J Biol Chem 276, 30942-7.
    

 
Book Chapters:

1. Androutsellis-Theotokis, A., Murase, S., Boyd, J. D., Park, D. M., Hoeppner, D. J., Ravin, R. & McKay, R. D. (2008). Generating neurons from stem cells. Methods Mol Biol 438, 31-8.
2. Androutsellis-Theotokis A., Rueger M.A., & McKay, RDG, Stem cell therapy for Parkinson’s Disease. In “CNS Regeneration: Basic Science and Clinical Advances”, Elsevier Press, 2008.
   

Magazine Columns:

1. Androutsellis-Theotokis A., & McKay, RDG, Generating and re-generating pluripotent and somatic stem cells in the laboratory and the body, To Vima Newspaper, Greece, 2008.

Curriculum vitae