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Division of Regenerative Medicine

Hirotaka James Okano, Professor

General Summary

Regenerative medicine is rapidly moving toward translation to clinical medicine. How- ever, a better understanding of the molecular pathways leading to human diseases is required for regenerative medicine to succeed. Good animal models will play a key role in research to increase our understanding of the diseases. Disease models in genetically engineered mice are extremely useful but do not always precisely recapitulate the patho- physiology of human disease, especially disorders of the central nervous system. We have recently attempted to create a transgenic primate model of human neurodegenerative diseases through forced expression of dominant mutant genes. On the other hand, induced pluripotent stem (iPS) cell technology has given us the ability to generate and expand various types of differentiated cell from patient

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derived cells; iPS cells are now being applied to cell therapy and being used to study of the mechanisms of dis- ease. Advances in disease modeling with patient

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derived cells and nonhuman primates will have an enormous affect on future opportunities and advances in biomedical research.

Research Activities

Therapeutic strategies for the damaged central nervous system

Recent advances in developmental and stem

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cell biology have made regeneration

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based therapies feasible for patients with damaged central nervous systems, including those with spinal cord injuries, Parkinson’s disease, or stroke.  Understanding and then con- trolling the appropriate regulatory mechanisms in neural stem cells (NSCs) will be impor- tant milestones in the development of regeneration

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based treatments for damaged central nervous system tissue. Previously, we observed how transplanted iPS cell–derived NSCs were integrated in the injured spinal cord and differentiated into various kinds of  cell, including neurons, astrocytes, and oligodendrocytes. Although the precise mecha- nism of symptomatic improvement remains unclear, NSC transplantation has promoted functional recovery in experimental studies in rats and nonhuman primates.

In

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vivo imaging technology applied to regenerative medicine

Bioluminescence imaging is an efficient and powerful method for longitudinal compari- son of cell survival and migration. Cell therapies can be more quickly optimized and refined with imaging, which is widely applicable to various types of regenerative medi- cine, including stem

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cell therapies. We used in

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vivo bioluminescence imaging to nonin- vasively assess the survival and residence time of transplanted NSCs at injury sites in liv- ing animals. Photon signals from these cells were detectable through normal tissues, such as bone and skin, with ultrasensitive cooled charged–coupled device cameras for 10

Research Activities 2011  The Jikei University School of Medicine

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months or more after transplantation into the injured spinal cords of mice.

Common marmoset as a primate disease model

The common marmoset (Callithrix jacchus) is becoming an increasingly popular primate animal model in biomedical research, because of its advantage of translation to geneti- cally similar human systems. Marmosets, because of their small size and high reproduc- tive rate, are suitable subjects for transgenic modification.  Recently, transgenic marmo- sets were successfully created by gene transduction into embryos; this animal model is genetically similar to humans and can be used to study human neurodegenerative dis- eases, such as Parkinson’s disease and amyotrophic lateral sclerosis. Good animal mod- els will play a key role in research to increase our understanding of the pathophysiology of neurodegenerative diseases. We have recently attempted to create a transgenic mar- moset model of human neurodegenerative diseases through forced expression of domi- nant mutant genes.

Publications

Shiozawa S, Kawai K, Okada Y, Tomioka I, Maeda T, Kanda A, Shinohara H, Suemizu H, Okano HJ, Sotomaru Y, Sasaki E, Okano H.

Gene targeting and subsequent site-specific trans- genesis at the β-actin (ACTB) locus in common marmoset embryonic stem cells. Stem Cells Dev.

2011; 20: 1587-99.

Hosoya M, Fujioka M, Matsuda S, Ohba H, Shibata S, Nakagawa F, Watabe T, Waka- bayashi K, Saga Y, Ogawa K, Okano HJ, Okano H. Expression and function of Sox21 during mouse cochlea development. Neurochem Res. 2011; 36: 1261-9.

Takagi T, Ishii K, Shibata S, Yasuda A, Sato M, Nagoshi N, Saito H, Okano HJ, Toyama Y, Okano H, Nakamura M. Schwann-spheres derived from injured peripheral nerves in adult mice-their in vitro characterization and therapeutic potential. PLoS One. 2011; 6: e21497.

Fukuda H, Mochizuki S, Abe H, Okano HJ, Hara-Miyauchi C, Okano H, Yamaguchi N, Nakayama M, D’Armiento J, Okada Y. Host- derived MMP-13 exhibits a protective role in lung metastasis of melanoma cells by local endostatin production. Br J Cancer. 2011; 105: 1615-24.

Yasuda A, Tsuji O, Shibata S, Nori S, Takano M, Kobayashi Y, Takahashi Y, Fujiyoshi K, Hara CM, Miyawaki A, Okano HJ, Toyama Y, Nakamura M, Okano H. Significance of remye- lination by neural stem/progenitor cells trans- planted into the injured spinal cord. Stem Cells.

2011; 29: 1983-94.

Sera T, Yokota H, Nakamura S, Uesugi K, Hoshino M, Yagi N, Ito T, Hikishima K, Okano HJ. Synchrotron refraction enhanced tomogra-

phy of an intact common marmoset (Callithrix jac- chus). Open Journal of Radiology. 2011; 1:

28-37.

Hara-Miyauchi C, Tsuji O, Hanyu A, Okada S, Yasuda A, Fukano T, Akazawa C, Nakamura M, Imamura T, Matsuzaki Y, Okano HJ, Mi- yawaki A, Okano H. Bioluminescent system for dynamic imaging of cell and animal behavior. Bio- chem Biophys Res Commun. 2012; 419: 188-93.

Lin ZY, Imamura M, Sano C, Nakajima R, Suzuki T, Yamadera R, Takehara Y, Okano HJ, Sasaki E, Okano H. Molecular signatures to define spermatogenic cells in common marmoset (Callithrix jacchus). Reproduction. 2012; 143:

597-609. Epub 2012 Feb 8.

Kuzumaki N, Suzuki A, Narita M, Hosoya T, Nagasawa A, Imai S, Yamamizu K, Morita M, Nagase H, Okada Y, Okano HJ, Yamashita JK, Okano H, Suzuki T, Narita M. Effect of k-opi- oid receptor agonist on the growth of non-small cell lung cancer (NSCLC) cells. Br J Cancer.

2012; 106: 1148-52.

Takahashi Y, Tsuji O, Kumagai G, Hara Miyau- chi C, Okano HJ, Miyawaki A, Toyama Y, Okano H, Nakamura M. Comparative study of methods for administering neural stem/progenitor cells to treat spinal cord injury in mice. Cell Trans- plant. 2011; 20: 727-39.

Hikishima K, Quallo MM, Komaki Y, Yamada M, Kawai K, Momoshima S, Okano HJ, Sasaki E, Tamaoki N, Lemon RN, Iriki A, Okano H.

Population-averaged standard template brain atlas for the common marmoset (Callithrix jacchus).

Neuroimage. 2011; 54: 2741-9.

Research Activities 2011  The Jikei University School of Medicine

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