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

Osahiko Tsuji, Kyoko Miura, Yohei Okada, Kanehiro Fujiyoshi, Masahiko Mukaino, Narihito Nagoshi, Kazuya Kitamura, Gentaro Kumagai, Makoto Nishino, Shuta Tomisato, Hisanobu Higashi, Toshihiro Nagai, Hiroyuki Katoh, Kazuhisa Kohda, Yumi Matsuzaki, Michisuke Yuzaki, Eiji Ikeda, Yoshiaki Toyama, Masaya Nakamura, Shinya Yamanaka & 1 others Hideyuki Okano

Research output: Contribution to journalArticle

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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 amouse 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 iPSderived 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 preevaluated safe iPS clone-derived neural stem/progenitor cells may be a promising cell source for transplantation therapy for SCI.

Original languageEnglish
Pages (from-to)12704-12709
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume107
Issue number28
DOIs
Publication statusPublished - 13-07-2010

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Induced Pluripotent Stem Cells
Spinal Cord Injuries
Teratoma
Cell Transplantation
Transplantation
Severe Combined Immunodeficiency
Neural Stem Cells
Recovery of Function
Oligodendroglia
Cell- and Tissue-Based Therapy
Astrocytes
Spinal Cord
Stem Cells
Therapeutics
Clone Cells
Safety
Neurons
Wounds and Injuries
Brain
Neoplasms

All Science Journal Classification (ASJC) codes

  • General

Cite this

Tsuji, Osahiko ; Miura, Kyoko ; Okada, Yohei ; Fujiyoshi, Kanehiro ; Mukaino, Masahiko ; Nagoshi, Narihito ; Kitamura, Kazuya ; Kumagai, Gentaro ; Nishino, Makoto ; Tomisato, Shuta ; Higashi, Hisanobu ; Nagai, Toshihiro ; Katoh, Hiroyuki ; Kohda, Kazuhisa ; Matsuzaki, Yumi ; Yuzaki, Michisuke ; Ikeda, Eiji ; Toyama, Yoshiaki ; Nakamura, Masaya ; Yamanaka, Shinya ; Okano, Hideyuki. / Therapeutic potential of appropriately evaluated safe-induced pluripotent stem cells for spinal cord injury. In: Proceedings of the National Academy of Sciences of the United States of America. 2010 ; Vol. 107, No. 28. pp. 12704-12709.
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Tsuji, O, Miura, K, Okada, Y, Fujiyoshi, K, Mukaino, M, Nagoshi, N, Kitamura, K, Kumagai, G, Nishino, M, Tomisato, S, Higashi, H, Nagai, T, Katoh, H, Kohda, K, Matsuzaki, Y, Yuzaki, M, Ikeda, E, Toyama, Y, Nakamura, M, Yamanaka, S & Okano, H 2010, 'Therapeutic potential of appropriately evaluated safe-induced pluripotent stem cells for spinal cord injury', Proceedings of the National Academy of Sciences of the United States of America, vol. 107, no. 28, pp. 12704-12709. https://doi.org/10.1073/pnas.0910106107

Therapeutic potential of appropriately evaluated safe-induced pluripotent stem cells for spinal cord injury. / Tsuji, Osahiko; Miura, Kyoko; Okada, Yohei; Fujiyoshi, Kanehiro; Mukaino, Masahiko; Nagoshi, Narihito; Kitamura, Kazuya; Kumagai, Gentaro; Nishino, Makoto; Tomisato, Shuta; Higashi, Hisanobu; Nagai, Toshihiro; Katoh, Hiroyuki; Kohda, Kazuhisa; Matsuzaki, Yumi; Yuzaki, Michisuke; Ikeda, Eiji; Toyama, Yoshiaki; Nakamura, Masaya; Yamanaka, Shinya; Okano, Hideyuki.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 107, No. 28, 13.07.2010, p. 12704-12709.

Research output: Contribution to journalArticle

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T1 - Therapeutic potential of appropriately evaluated safe-induced pluripotent stem cells for spinal cord injury

AU - Tsuji, Osahiko

AU - Miura, Kyoko

AU - Okada, Yohei

AU - Fujiyoshi, Kanehiro

AU - Mukaino, Masahiko

AU - Nagoshi, Narihito

AU - Kitamura, Kazuya

AU - Kumagai, Gentaro

AU - Nishino, Makoto

AU - Tomisato, Shuta

AU - Higashi, Hisanobu

AU - Nagai, Toshihiro

AU - Katoh, Hiroyuki

AU - Kohda, Kazuhisa

AU - Matsuzaki, Yumi

AU - Yuzaki, Michisuke

AU - Ikeda, Eiji

AU - Toyama, Yoshiaki

AU - Nakamura, Masaya

AU - Yamanaka, Shinya

AU - Okano, Hideyuki

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N2 - 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 amouse 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 iPSderived 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 preevaluated safe iPS clone-derived neural stem/progenitor cells may be a promising cell source for transplantation therapy for SCI.

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