Neural stem cell

Neural stem cell
Latin	cellula nervosa precursoria
Code	TH H2.00.01.0.00010

Neural stem cells (NSCs) are the self-renewing, multipotent cells that generate the main phenotypes of the nervous system. In 1989, Sally Temple described multipotent, self-renewing progenitor and stem cells in the subventricular zone of the mouse brain (Temple, S, Nature, 1989). In 1992, Brent A. Reynolds and Samuel Weiss were the first to isolate neural progenitor and stem cells from the adult striatal tissue, including the subventricular zone — one of the neurogenic areas — of adult mice brain tissue.^[1] In the same year the team of Constance Cepko and Evan Y. Snyder were the first to isolate multipotent cells from the mouse cerebellum and stable transfected them with the oncogene v-myc.^[2] Interestingly this molecule is one of the genes widely used now to reprogrammed adult non-stem cells into pluripotent stem cells. Since then, neural progenitor and stem cells have been isolated from various areas of the adult brain,^[3] including non-neurogenic areas, such as the spinal cord, and from various species including human.^[4]

Functions

Epidermal growth factor (EGF) and fibroblast growth factor (FGF) are mitogens that promote neural progenitor and stem cell growth in vitro, though other factors synthesized by the neural progenitor and stem cell populations are also required for optimal growth.^[5] It is hypothesized that neurogenesis in the adult brain originates from NSCs. The origin and identity of NSCs in the adult brain remain to be defined.

Function of Neural stem cells (NSC) during disease

NSCs have an important role during development producing the enormous diversity of neurons, astrocytes and oligodendrocytes in the developing CNS. They also have important role in adult animals, for instance in learning and hippocampal plasticity in the adult mice in addition to supplying neurons to the olfactory bulb in mice.

Notably the role of NSCs during diseases is now being elucidated by several research groups around the world. The responses during stroke, multiple sclerosis, parkinson's disease in humans and in model of these diseases is part of the current investigation. The results of this ongoing investigation may have future applications to treat human neurological diseases.

Neural stem cells have been shown to engage in migration and replacement of dying neurons in classical experiments performed by Sanjay Magavi and Jeffrey Macklis.^[6] Using a laser-induced damage of cortical layers, Magavi showed that SVZ neural progenitors expressing Doublecortin, a critical molecule for migration of neuroblasts, migrated long distances to the area of damage and differentiated into mature neurons expressing NeuN, a widely used neuronal marker. In addition Masato Nakafuku's group from Japan showed for the first time the role of hippocampal stem cells during stroke in mice.^[7] These results demonstrated that NSCs can engage in the adult brain as a results of injury. Furthermore, In 2004 based on early work of Evan Synder's group, that showed that NSCs migrate to brain tumors in a directed fashion, Jaime Imitola, M.D and colleagues from Harvard demonstrated for the first time, a molecular mechanism for the responses of NSCs to injury, they showed that chemokines released during injury such as SDF-1a were responsible for the directed migration of human and mouse NSCs to areas of injury in mice.^[8] Since then other molecules have been found to participate in the responses of NSCs to Injury. All these results have been widely reproduced and expanded by other investigators joining the classical work of Altman and Sidman in 1960's as evidence of the responses of adult NSCs activities and neurogenesis during homeostasis and injury. The search for additional mechanisms that operate in the injury environment and how they influence the responses of NSCs during acute and chronic disease is matter of intense research.^[9]

Assay

Neural stem cells are routinely studied in vitro using a method referred to as the Neurosphere Assay (or Neurosphere culture system), first developed by Reynolds and Weiss.^[1] Neurospheres are intrinsically heterogeneous cellular entities almost entirely formed by a small fraction (1 to 5%) of slowly dividing neural stem cells and by their progeny, a population of fast-dividing nestin-positive progenitor cells.^[1][10][11] The total number of these progenitors determines the size of a neurosphere and, as a result, disparities in sphere size within different neurosphere populations may reflect alterations in the proliferation, survival and/or differentiation status of their neural progenitors. Indeed, Leone et al. (2005) have reported that loss of β1-integrin in a neurosphere culture does not significantly affect the capacity of β1-integrin deficient stem cells to form new neurospheres, but it influences the size of the neurosphere: β1-integrin deficient neurospheres were overall smaller due to increased cell death and reduced proliferation.^[12]

While the Neurosphere Assay has been the method of choice for isolation, expansion and even the enumeration of neural stem and progenitor cells, several recent publications have highlighted some of the limitations of the neurosphere culture system as a method for determining neural stem cell frequencies.^[13] In collaboration with Reynolds, STEMCELL Technologies has developed a collagen-based assay, called the Neural Colony-Forming Cell (NCFC) Assay, for the quantification of neural stem cells. Importantly, this assay allows discrimination between neural stem and progenitor cells.^[14]

Neural Stem Cell Institutes

The damaged central nervous system (CNS) tissue has very limited regenerative and repair capacity so that loss of neurological function is often chronic and progressive. Cell replacement from stem cells is being actively pursued as a therapeutic option. Recently in 2009, a research institute dedicated solely to translating neural stem research into therapies for patients was created outside of Albany, NY, The Neural Stem Cell Institute.

See also

• Neurogenesis
• Stem cell

References

1. ^ ^{a b c} Reynolds, B.; Weiss, S (1992). "Generation of neurons and astrocytes from isolated cells of the adult mammalian central nervous system". Science 255 (5052): 1707–10. Bibcode 1992Sci...255.1707R. doi:10.1126/science.1553558. PMID 1553558. 
2. ^ Snyder, Evan Y.; Deitcher, David L.; Walsh, Christopher; Arnold-Aldea, Susan; Hartwieg, Erika A.; Cepko, Constance L. (1992). "Multipotent neural cell lines can engraft and participate in development of mouse cerebellum". Cell 68 (1): 33–51. doi:10.1016/0092-8674(92)90204-P. PMID 1732063. 
3. ^ Zigova, Tanja; Sanberg, Paul R.; Sanchez-Ramos, Juan Raymond, eds (2002). Neural stem cells: methods and protocols. Humana Press. ISBN 978-0-89603-964-3. http://books.google.com/books?id=4-KHzWwgMKEC. Retrieved 18 April 2010. ^{[page needed]}
4. ^ Taupin, Philippe; Gage, Fred H. (2002). "Adult neurogenesis and neural stem cells of the central nervous system in mammals". Journal of Neuroscience Research 69 (6): 745–9. doi:10.1002/jnr.10378. PMID 12205667. 
5. ^ Taupin, Philippe; Ray, Jasodhara; Fischer, Wolfgang H; Suhr, Steven T; Hakansson, Katarina; Grubb, Anders; Gage, Fred H (2000). "FGF-2-Responsive Neural Stem Cell Proliferation Requires CCg, a Novel Autocrine/Paracrine Cofactor". Neuron 28 (2): 385–97. doi:10.1016/S0896-6273(00)00119-7. PMID 11144350. 
6. ^ MacKlis, Jeffrey D.; Magavi, Sanjay S.; Leavitt, Blair R. (2000). "Induction of neurogenesis in the neocortex of adult mice". Nature 405 (6789): 951–5. doi:10.1038/35016083. PMID 10879536. 
7. ^ Nakatomi, Hirofumi; Kuriu, Toshihiko; Okabe, Shigeo; Yamamoto, Shin-Ichi; Hatano, Osamu; Kawahara, Nobutaka; Tamura, Akira; Kirino, Takaaki et al. (2002). "Regeneration of Hippocampal Pyramidal Neurons after Ischemic Brain Injury by Recruitment of Endogenous Neural Progenitors". Cell 110 (4): 429–41. doi:10.1016/S0092-8674(02)00862-0. PMID 12202033. 
8. ^ Imitola, Jaime; Raddassi K, Park KI, Mueller FJ, Nieto M, Teng YD, Frenkel D, Li J, Sidman RL, Walsh CA, Snyder EY, Khoury SJ. (Dec 28). "Directed migration of neural stem cells to sites of CNS injury by the stromal cell-derived factor 1alpha/CXC chemokine receptor 4 pathway.". PNAS 101: 18117–22. doi:10.1073/pnas.0408258102. PMC 536055. PMID 15608062. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=536055. 
9. ^ Sohur US, US.; Emsley JG, Mitchell BD, Macklis JD. (Sep 29). "Adult neurogenesis and cellular brain repair with neural progenitors, precursors and stem cells.". Philos Trans R Soc Lond B Biol Sci. 361: 1477–97.. 
10. ^ Campos, L. S.; Leone, DP; Relvas, JB; Brakebusch, C; Fässler, R; Suter, U; Ffrench-Constant, C (2004). "β1 integrins activate a MAPK signalling pathway in neural stem cells that contributes to their maintenance". Development 131 (14): 3433–44. doi:10.1242/dev.01199. PMID 15226259. 
11. ^ Lobo, M. V. T.; Alonso, F. J. M.; Redondo, C.; Lopez-Toledano, M. A.; Caso, E.; Herranz, A. S.; Paino, C. L.; Reimers, D. et al. (2003). "Cellular Characterization of Epidermal Growth Factor-expanded Free-floating Neurospheres". Journal of Histochemistry & Cytochemistry 51 (1): 89–103. doi:10.1177/002215540305100111. PMID 12502758. 
12. ^ Leone, D. P.; Relvas, JB; Campos, LS; Hemmi, S; Brakebusch, C; Fässler, R; Ffrench-Constant, C; Suter, U (2005). "Regulation of neural progenitor proliferation and survival by β1 integrins". Journal of Cell Science 118 (12): 2589–99. doi:10.1242/jcs.02396. PMID 15928047. 
13. ^ Singec, Ilyas; Knoth, Rolf; Meyer, Ralf P; MacIaczyk, Jaroslaw; Volk, Benedikt; Nikkhah, Guido; Frotscher, Michael; Snyder, Evan Y (2006). "Defining the actual sensitivity and specificity of the neurosphere assay in stem cell biology". Nature Methods 3 (10): 801–6. doi:10.1038/nmeth926. PMID 16990812. 
14. ^ Louis, Sharon A.; Rietze, Rodney L.; Deleyrolle, Loic; Wagey, Ravenska E.; Thomas, Terry E.; Eaves, Allen C.; Reynolds, Brent A. (2008). "Enumeration of Neural Stem and Progenitor Cells in the Neural Colony-Forming Cell Assay". Stem Cells 26 (4): 988–96. doi:10.1634/stemcells.2007-0867. PMID 18218818.