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Neurons and glial cells are major cells constituting the central nervous system and are generated from a common precursor cells called "neural stem cell". Neural stem cells are currently attracting close attention because they can differentiate not only into neurons and glial cells but also into any other cell constituting the human body, implying a probability that neural stem cells could be applicable to any type of regenerative medicine (Fig. 1). Neural stem cells are found also in the adult brain (Fig. 2, green); they continue producing neurons and glial cells every day, suggesting that the new neurons produced by them are involved in learning and other functions. The differentiation of neural stem cells is regulated in a sophisticated manner both temporally and spatially, involving not only crosstalks between extracellular cues (cytokine signaling, etc.; Fig. 3) but also the intracellular epigenetic programs (DNA methylation, and so on) (Fig. 4). Our laboratory is attempting to elucidate the mechanism for fate specification of neural stem cells and to apply the findings from such studies to facilitate the repair and regeneration of injured nerve functions.
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- Clarification of epigenetic mechanisms for fate determination of neuronal stem cells
It is becoming apparent that epigenetics (e.g., DNA methylation and chromatin-structure conversion) is deeply involved as an inherent cell program in the regulation of neural stem cell differentiation. We are studying what epigenetic changes take place in cells when the fate of neuronal stem cells is specified and how these changes work in cooperation with extracellular factors to determine the type of cells generated from neural stem cells.
- Clarification of mechanisms for fate determination of neuronal stem cells using ES cells
Embryonic stem (ES) cells are pluripotent cells which can differentiate into any cell seen in adult organisms. Efficient induction of neural cells from ES cells is interesting from the standpoint of basic biology and it is expected to be applicable to repair of injured nerves and other purposes. We attempt to elucidate the mechanism for regulation of ES cell differentiation into neural cells.
- Regeneration of injured nerves by neural stem cell transplantation
On the basis of the findings from studies 1) and 2) mentioned above, we attempt to transplant neural stem cells capable of efficiently producing neural cells into mouse models of nerve injury and so on and to evaluate the usefulness of this technique in stimulating recovery in nerve function.
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- Abematsu et al., J Clin Invest., 120, 3255-3266, 2010
- Muotri et al., Nature, 468, 443-446, 2010
- Juliandi et al., Curr Opin Neurobiol., 20, 408-415, 2010
- Kohyama et al., J Cell Biol., 189, 159-170, 2010
- Asano et al., Stem Cells, 27, 2744-2752, 2009
- Tsujimura et al., Exp Neurol, 219, 104-111, 2009
- Namihira et al., Dev Cell, 16, 245-255, 2009
- Kohyama et al., Proc Natl Acad Sci USA, 105, 18012-18017, 2008
- Hsieh, Nakashima et al., Proc Natl Acad Sci USA, 101, 16659-16664, 2004.
- Nakashima et al., Nature Med, 10, 23-24, 2004
- Takizawa, Nakashima et al., Dev Cell, 1, 749-758, 2001
- Nakashima et al., Science, 284, 479-82, 1999
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Fig. 1 Differentiation of neural stem cells into cells in various organs
Fig. 2 Neural stem cells found in adult rat hippocampus
Fig. 3 Regulation of gene expression by crosstalks between extracellular factors
Fig. 4 DNA methylation involved in fate regulation of neural stem cells
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