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特別講演1 岡野栄之

"Brain Science using iPScell technology and transgenic non-human primates."

岡野栄之先生
(慶應義塾大学医学部 生理学教室)

There is an increasing interest of induced pluripotent stem (iPS) cells as a source of neural

 Okano Photo.JPG

stem/progenitor cells (NS/PCs), which can be obtained from patients' own somatic cells. We found that mouse iPS cells can be induced for NS/PCs by the same method for neural differentiation of mouse ES cells. In order to obtain safeness of iPS cells-derived NS/PCs, we examined various factors who could affect the tumorigenic ability of iPS cells-derived NS/PCs, including the origin of iPS cells, usage of c-Myc transgene or usage of genetic selection using drug resistant gene. We also found that the origin of the iPS cells is the crucial factor for predicting the safety issue and that the content of undifferentiated cells (i.e. differentiation-resistant cells) within NS/PCs highly correlated with their tumorigenic activity. When we examined the therapeutic ability of NS/PCs-derived from pre-evaluated non-tumorigenic iPS cells for injured spinal cord using mouse model, we found that the pre-evaluated iPS-derived NS/PCs and ES-derived ones show similar therapeutic effects upon spinal cord injury (SCI).

There is another advantage in the iPS cells technology, which might be used to fill the gaps in modelling of pathophysiology of human neurological diseases by creating a novel approach known as "disease in a dish".  Parkinson's disease (PD) involves degeneration of the dopaminergic neurons within the substantia nigra, followed by other degenerative changes throughout the brain. Some of the PDs are caused familiarly by genetic mutations, although more than 90% of PD cases are sporadic. However, the dysfunctions of mitochondria and abnormal alpha-synuclein accumulation as well as Lewy Body (LB) formation could be the common mechanisms of familial and sporadic PDs. Recently, we generated iPS cells from several PD patients and showed pathological changes in PD iPS cells-derived neurons in comparison with the postmortem brain of the same patient. In the present lecture, I also talk about the advantage of iPS cells-technology to study the pathophysiology of other neurodegenerative diseases including Alzheimer disease and developmental disorders affecting central nervous system. These new models not only revealing the mechanistic insights of PD pathophysiology, but also help us to clarify novel targets of drug screening and modifying therapies of PDs. I also wish to talk about our recent results on iPS-based cell therapy for spinal cord injuries.

In this lecture, I wish to discuss the future direction of iPS cell research and new trends of brain science using transgenic technologies of non-human primates.

 Okano Fig.jpg

 

References

1)          Naka H, Nakamura S, Shimazaki T, Okano H: Requirement for COUP-TFI and II in the temporal specification of neural stem cells in central nervous system development. Nature Neurosci 11 (9): 1014-1023, 2008

2)          Okada Y, Matsumoto A, Shimazaki T, Enoki R, Koizumi A, Ishii S, Itoyama Y, Sobue G, Okano H. Spatio-temporal recapitulation of central nervous system development by ES cell-derived neural stem/progenitor cells. Stem Cells. 26; 3086-3098, 2008.

3)          Sasaki E, Suemizu H, Shimada A, Hanazawa K, Oiwa R, Kamioka M, Sotomaru Y, Hirakawa R, Eto T, Shiozawa S, Maeda T, Ito R, Kito C, Yagihashi C, Kawai K, Miyoshi H, Tanioka Y, Tamaoki N, Habu S, Okano H, Nomura T. : Generation of transgenic non-human primates with germ line transmission. Nature, 459(7246):523-527, 2009. (*H. Okano is the corresponding author in this paper)

4)          Miura K, Okada Y, Aoi T, Okada A, Takahashi K, Okita K, Nakagawa M, Koyanagi M, Tanabe K, Ohnuki M, Ogawa D, Ikeda E, Okano H, Yamanaka S.: Variation in the safety of inducedpluripotent stem cell lines Nature Biotechnol. 27(8):743-745, 2009. (*H. Okano is the corresponding author in this paper)

5)         Tsuji O, Miura K, Okada Y, Fujiyoshi K, Nagoshi N, Kitamura K, Kumagai G, Mukaino M, Nishino M, Tomisato S, Higashi H, Ikeda E, Nagai T, Kohda K, Takahashi K, Okita K, Katoh H, Matsuzaki Y, Yuzaki M, Toyama Y, Nakamura M, Yamanaka S and Okano H.: Therapeutic effect of the appropriatelly evaluated 'safe' iPS cells for spinal cord injury. Proc.Natl.Acad.Sci.USA 107(28):12704-12709, 2010.

6)         Kuwako K., Kakumoto K, Imai T, Igarashi M, Hamakubo T, Sakakibara S, Tessier-Lavigne M, Okano HJ, Okano H.: Neural RNA-binding protein Musashi1 controls midline crossing of precerebellar neurons through post-transcriptional regulation of Robo3/Rig-1 expression. Neuron 67(3):407-421, 2010.

7)         Fujioka M, Tokano H, Fujioka-Shiina K, Okano H, Edge A.S.B.: Cre/lox mediated in vivo mosaic cell ablation to generate novel models for early stages of degenerative disease and tissue repair. J. Clin. Invest. 121(6):2462-2469, 2011.

8)         Ishizuka K, Kamiya A, Oh EC, Kanki H, Sehadri S, Robinson J, Murdoch H, Dunlop AJ, Kubo KI, Furukori K, Huang B, Zeledon M, Hayashi-Takagi A, Okano H, Nakajima K, Houslay MD, Katsanis N, Sawa A. :DISC1-dependent switch from progenitor proliferation to migration in the developing cortex. Nature. 473(7345):92-96, 2011.

9)         Yagi T, Ito D, Okada Y, Akamatsu W, Nihei Y, Yoshizaki T, Yamanaka S, Okano H, Suzuki N. Modeling familial Alzheimer's disease with induced pluripotent stem cells. Hum Mol Genet. 20(23):4530-4539, 2011.

10)      Nori S, Okada Y, Yasuda A, Tsuji O, Takahashi Y, Kobayashi Y, Fujiyoshi K, Koike M, Uchiyama Y, Ikeda E, Toyama Y, Yamanaka S, Masaya N, Okano H.: Grafted human induced pluripotent stem cell-derived neurospheres promotes motor functional recovery after spinal cord injury in mice. Proc.Natl.Acad.Sci.USA 108(40):16825-16830, 2011.

 



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