The Role of eNSCs in Neurodegenerative Disease

Wellcome Trust Centre for Stem Cell Research, University of Cambridge, Cambridge, UK.
Molecular Neurobiology (Impact Factor: 5.14). 07/2012; 46(3). DOI: 10.1007/s12035-012-8303-8
Source: PubMed


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 neural stem cells in the central nervous system may have adopted 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.

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    • "The role of the STAT3-Ser/Hes3 signaling axis in controlling NSC number in vitro and in vivo makes it a potential pharmacological target in neurodegenerative disease therapy (Kittappa et al., 2012). Several diverse treatments that promote the pathway exhibit similar results on cultured cell number, including ligands of the Notch (Delta4, Jagged1) and Tie2 (Angiopoietin 2) receptors, basic FGF, and insulin (Androutsellis-Theotokis et al., 2006, 2008b, 2009, 2010a,b). "
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    ABSTRACT: Stem cells, by definition, are able to both self-renew (give rise to more cells of their own kind) and demonstrate multipotential (the ability to differentiate into multiple cell types). To accommodate this unique dual ability, stem cells interpret signal transduction pathways in specialized ways. Notable examples include canonical and non-canonical branches of the Notch signaling pathway, with each controlling different downstream targets (e.g., Hes1 vs. Hes3) and promoting either differentiation or self-renewal. Similarly, stem cells utilize STAT3 signaling uniquely. Most mature cells studied thus far rely on tyrosine phosphorylation (STAT3-Tyr) to promote survival and growth; in contrast, STAT3-Tyr induces the differentiation of neural stem cells (NSCs). NSCs use an alternative phosphorylation site, STAT3-Ser, to regulate survival and growth, a site that is largely redundant for this function in most other cell types. STAT3-Ser regulates Hes3, and together they form a convergence point for several signals, including Notch, Tie2, and insulin receptor activation. Disregulation and manipulation of the STAT3-Ser/Hes3 signaling pathway is important in both tumorigenesis and regenerative medicine, and worthy of extensive study.
    Frontiers in Physiology 10/2013; 4:273. DOI:10.3389/fphys.2013.00273 · 3.53 Impact Factor
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    • "In this work, we focused on Hes3 expression in order to measure the effects of treatments on the putative endogenous neural stem cell/progenitor cell population in the adult mouse and rat brains. In the adult brain, Delta4 and Angiopoietin 2 (Ang2) are produced by vascular endothelial cells, with which Hes3+ cells physically associate, suggesting that the activation of Hes3+ cells by the exogenous factors used here may reflect a natural regenerative response of the adult brain to injury [71]. "
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    ABSTRACT: The adult hippocampus is involved in learning and memory. As a consequence, it is a brain region of remarkable plasticity. This plasticity exhibits itself both as cellular changes and neurogenesis. For neurogenesis to occur, a population of local stem cells and progenitor cells is maintained in the adult brain and these are able to proliferate and differentiate into neurons which contribute to the hippocampal circuitry. There is much interest in understanding the role of immature cells in the hippocampus, in relation to learning and memory. Methods and mechanisms that increase the numbers of these cells will be valuable in this research field. We show here that single injections of soluble factors into the lateral ventricle of adult rats and mice induces the rapid (within one week) increase in the number of putative stem cells/progenitor cells in the hippocampus. The established progenitor marker Sox2 together with the more recently established marker Hes3, were used to quantify the manipulation of the Sox2/Hes3 double-positive cell population. We report that in both adult rodent species, Sox2+/Hes3+ cell numbers can be increased within one week. The most prominent increase was observed in the hilus of the dentate gyrus. This study presents a fast, pharmacological method to manipulate the numbers of endogenous putative stem cells/progenitor cells. This method may be easily modified to alter the degree of activation (e.g. by the use of osmotic pumps for delivery, or by repeat injections through implanted cannulas), in order to be best adapted to different paradigms of research (neurodegenerative disease, neuroprotection, learning, memory, plasticity, etc).
    PLoS ONE 12/2012; 7(12):e51630. DOI:10.1371/journal.pone.0051630 · 3.23 Impact Factor
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    Molecular Neurobiology 08/2012; 46(3). DOI:10.1007/s12035-012-8323-4 · 5.14 Impact Factor
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