Grafted human-induced pluripotent stem-cell-derived neurospheres promote motor functional recovery after spinal cord injury in mice

Satoshi Nori, Yohei Okada, Akimasa Yasuda, Osahiko Tsuji, Yuichiro Takahashi, Yoshiomi Kobayashi, Kanehiro Fujiyoshi, Masato Koike, Yasuo Uchiyama, Eiji Ikeda, Yoshiaki Toyama, Shinya Yamanaka, Masaya Nakamura, Hideyuki Okano

Research output: Contribution to journalArticle

286 Citations (Scopus)

Abstract

Once their safety is confirmed, human-induced pluripotent stem cells (hiPSCs), which do not entail ethical concerns, may become a preferred cell source for regenerative medicine. Here, we investigated the therapeutic potential of transplanting hiPSC-derived neurospheres (hiPSC-NSs) into nonobese diabetic (NOD)-severe combined immunodeficient (SCID) mice to treat spinal cord injury (SCI). For this, we used a hiPSC clone (201B7), established by transducing four reprogramming factors (Oct3/4, Sox2, Klf4, and c-Myc) into adult human fibroblasts. Grafted hiPSC-NSs survived, migrated, and differentiated into the three major neural lineages (neurons, astrocytes, and oligodendrocytes) within the injured spinal cord. They showed both cell-autonomous and noncellautonomous (trophic) effects, including synapse formation between hiPSC-NS-derived neurons and host mouse neurons, expression of neurotrophic factors, angiogenesis, axonal regrowth, and increased amounts of myelin in the injured area. These positive effects resulted in significantly better functional recovery compared with vehicle-treated control animals, and the recovery persisted through the end of the observation period, 112 d post-SCI. No tumor formation was observed in the hiPSC-NS-grafted mice. These findings suggest that hiPSCs give rise to neural stem/progenitor cells that support improved function post-SCI and are a promising cell source for its treatment.

Original languageEnglish
Pages (from-to)16825-16830
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume108
Issue number40
DOIs
Publication statusPublished - 2011 Oct 4

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Induced Pluripotent Stem Cells
Spinal Cord Injuries
Neurons
Regenerative Medicine
SCID Mice
Neural Stem Cells
Oligodendroglia
Nerve Growth Factors
Myelin Sheath
Astrocytes
Synapses
Spinal Cord
Stem Cells
Clone Cells
Fibroblasts
Observation
Safety
Therapeutics

Keywords

  • Cell transplantation
  • Neurotrauma
  • Stem-cell-based medicine
  • Synaptic connection

ASJC Scopus subject areas

  • General

Cite this

Grafted human-induced pluripotent stem-cell-derived neurospheres promote motor functional recovery after spinal cord injury in mice. / Nori, Satoshi; Okada, Yohei; Yasuda, Akimasa; Tsuji, Osahiko; Takahashi, Yuichiro; Kobayashi, Yoshiomi; Fujiyoshi, Kanehiro; Koike, Masato; Uchiyama, Yasuo; Ikeda, Eiji; Toyama, Yoshiaki; Yamanaka, Shinya; Nakamura, Masaya; Okano, Hideyuki.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 108, No. 40, 04.10.2011, p. 16825-16830.

Research output: Contribution to journalArticle

Nori, S, Okada, Y, Yasuda, A, Tsuji, O, Takahashi, Y, Kobayashi, Y, Fujiyoshi, K, Koike, M, Uchiyama, Y, Ikeda, E, Toyama, Y, Yamanaka, S, Nakamura, M & Okano, H 2011, 'Grafted human-induced pluripotent stem-cell-derived neurospheres promote motor functional recovery after spinal cord injury in mice', Proceedings of the National Academy of Sciences of the United States of America, vol. 108, no. 40, pp. 16825-16830. https://doi.org/10.1073/pnas.1108077108
Nori, Satoshi ; Okada, Yohei ; Yasuda, Akimasa ; Tsuji, Osahiko ; Takahashi, Yuichiro ; Kobayashi, Yoshiomi ; Fujiyoshi, Kanehiro ; Koike, Masato ; Uchiyama, Yasuo ; Ikeda, Eiji ; Toyama, Yoshiaki ; Yamanaka, Shinya ; Nakamura, Masaya ; Okano, Hideyuki. / Grafted human-induced pluripotent stem-cell-derived neurospheres promote motor functional recovery after spinal cord injury in mice. In: Proceedings of the National Academy of Sciences of the United States of America. 2011 ; Vol. 108, No. 40. pp. 16825-16830.
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