Therapeutic potential of appropriately evaluated safe-induced pluripotent stem cells for spinal cord injury

Therapeutic potential of appropriately evaluated safe-induced pluripotent stem cells for spinal cord injury
Osahiko Tsujia,b,1, Kyoko Miuraa,c,1, Yohei Okadaa,d, Kanehiro Fujiyoshia,b, Masahiko Mukainoa,e, Narihito Nagoshia,b,f, Kazuya Kitamuraa,b, Gentaro Kumagaia,g, Makoto Nishinoa, Shuta Tomisatoa, Hisanobu Higashia, Toshihiro Nagaih, Hiroyuki Katoha,b,f, Kazuhisa Kohdaa, Yumi Matsuzakia, Michisuke Yuzakia, Eiji Ikedai,j, Yoshiaki Toyamab, Masaya Nakamurab,2, Shinya Yamanakac, and Hideyuki Okanoa,2
+ Author Affiliations

Departments of aPhysiology and
bOrthopedic Surgery, School of Medicine, Keio University, Shinjuku, Tokyo 160-8582, Japan;
cCenter for Induced Pluripotent Stem Cell Research and Application, Kyoto University, Kyoto 606-8507, Japan;
dKanrinmaru-Project and
Departments of eRehabilitation Medicine,
hElectron Microscope Laboratory, and
iPathology, School of Medicine, Keio University, Tokyo 160-8582, Japan;
fDepartment of Orthopedic Surgery, National Hospital Organization, Murayama Medical Center, Tokyo 208-0011, Japan;
gDepartment of Orthopedic Surgery, Graduate School of Medicine, Hirosaki University, Aomori 036-8560, Japan; and
jDepartment of Pathology, Graduate School of Medicine, Yamaguchi University, Yamaguchi 755-8505, Japan
Edited by Fred Gage, Salk Institute, San Diego, CA, and approved June 3, 2010 (received for review September 3, 2009)

↵1O.T. and K.M. contributed equally to this work.

Abstract
Various types of induced pluripotent stem (iPS) cells have been established by different methods, and each type exhibits different biological properties. Before iPS cell-based clinical applications can be initiated, detailed evaluations of the cells, including their differentiation potentials and tumorigenic activities in different contexts, should be investigated to establish their safety and effectiveness for cell transplantation therapies. Here we show the directed neural differentiation of murine iPS cells and examine their therapeutic potential in a mouse spinal cord injury (SCI) model. “Safe” iPS-derived neurospheres, which had been pre-evaluated as nontumorigenic by their transplantation into nonobese diabetic/severe combined immunodeficiency (NOD/SCID) mouse brain, produced electrophysiologically functional neurons, astrocytes, and oligodendrocytes in vitro. Furthermore, when the safe iPS-derived neurospheres were transplanted into the spinal cord 9 d after contusive injury, they differentiated into all three neural lineages without forming teratomas or other tumors. They also participated in remyelination and induced the axonal regrowth of host 5HT+ serotonergic fibers, promoting locomotor function recovery. However, the transplantation of iPS-derived neurospheres pre-evaluated as “unsafe” showed robust teratoma formation and sudden locomotor functional loss after functional recovery in the SCI model. These findings suggest that pre-evaluated safe iPS clone-derived neural stem/progenitor cells may be a promising cell source for transplantation therapy for SCI.
http://www.pnas.org/content/107/28/12704

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To whom correspondence may be addressed. E-mail: hidokano@sc.itc.keio.ac.jp or masa@sc.itc.keio.ac.jp. Author contributions: O.T., K.M., M. Nakamura, S.Y., and H.O. designed research; O.T., K.M., Y.O., K.F., M.M., N.N., K. Kitamura, G.K., M. Nishino, S.T., H.H., T.N., H.K., E.I., and H.O. performed research; O.T. and K.M. contributed new reagents/analytic tools; O.T., K.M., Y.O., K.F., M.M., N.N., K. Kitamura, G.K., H.K., K. Kohda, Y.M., M.Y., E.I., Y.T., M. Nakamura, S.Y., and H.O. analyzed data; and O.T., K.M., Y.O., K.F., H.K., E.I., M. Nakamura, and H.O. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
This article contains supporting information online at
www.pnas.org/lookup/suppl/doi:10.1073/pnas.0910106107/-/DCSupplemental.