The Role of eNSCs in Neurodegenerative Disease Raja Kittappa & Stefan R. Bornstein & Andreas Androutsellis-Theotokis Received: 6 July 2012 / Accepted: 9 July 2012 / Published online: 21 July 2012 # Springer Science+Business Media, LLC 2012 Abstract Recent progress in biology has shown that many if not all adult tissues contain a population of stem cells. It is believed that these cells are involved in the regeneration of the tissue or organ in which they reside as a response to the natural turnover of differentiated cells or to injury. In the adult mammalian brain, stem cells in the subventricular zone and the dentate gyrus may also play a role in the replacement of neurons. A positive beneficial response to injury does not necessarily require cell replacement. New findings suggest that some populations of endogenous neu- ral stem cells in the central nervous system may have adop- ted a function different from cell replacement and are involved in the protection of neurons in diverse paradigms of disease and injury. In this article, we will focus on the immature cell populations of the central nervous system and the signal transduction pathways that regulate them which suggest new possibilities for their manipulation in injury and disease. Keywords eNSCs . Neurodegenerative disease . Stem cell biology Introduction There is great excitement surrounding stem cell biology and potential cell therapies to treat complex, degenerative diseases. Numerous degenerative diseases (including Alzheimer's dis- ease, Parkinson's disease, Huntington's disease, motor neuron diseases, etc.) affect the aging nervous system and come at a tremendous personal cost to individuals and their families and a significant financial burden to the public. The most obvious question with regard to cell therapies is the source for cell replacement. Should the focus be on embryonic, fetal, or adult stem cells? Which source can best avoid the problems of immuno-compatibility, inefficient cell expansion in culture, induction of cancer, ethical issues, etc.? Recent breakthroughs have tried to tackle some problems through new means of deriving cloned human embryonic stem cell lines and the reprogramming of adult skin fibroblasts into an embryonic stem cell-like state. A more fundamental impediment for cell therapy in neu- rodegenerative disease is the complex cytoarchitecture of the central nervous system (CNS). In Parkinson's disease (PD), for example, dopamine neurons that extend from the substantia nigra to the striatum, several centimeters away, die over long periods of time. Cell transplantation (generat- ed by any method) results in their placement in one area (usually the striatum) where they act as dopamine pumps and do not recapitulate the functional nigrostriatal circuitry [1]. This problem may not be as serious in other tissues or organs with a much simpler organization where cell con- nectivity is less complex (e.g., liver and pancreas) or where stem cells can easily access their niche (e.g., bone marrow). Another consideration of cell therapy comes from recent evidence from PD and amyotrophic lateral sclerosis showing that neurodegeneration is not necessarily cell-autonomous; fur- thermore, in several cases, grafted cells in PD patients acquire the disease (assessed by the presence of “Lewy bodies”)[1–4]. While the replacement of compromised cells can alleviate disease symptoms, it does not necessarily halt disease R. Kittappa Wellcome Trust Centre for Stem Cell Research, University of Cambridge, Cambridge, UK S. R. Bornstein : A. Androutsellis-Theotokis (*) Department of Medicine, University of Dresden, Dresden, Germany e-mail: Andreas.Theotokis@uniklinikum-dresden.de S. R. Bornstein : A. Androutsellis-Theotokis Center for Regenerative Therapies Dresden, Dresden, Germany A. Androutsellis-Theotokis European Brain Research Institute, Rome, Italy Mol Neurobiol (2012) 46:555–562 DOI 10.1007/s12035-012-8303-8