title: Pre-evaluated safe human iPSC-derived neural stem cells promote functional recovery after spinal cord injury in common marmoset without tumorigenicity.
abstract: Murine and human iPSC-NS/PCs (induced pluripotent stem cell-derived neural stem/progenitor cells) promote functional recovery following transplantation into the injured spinal cord in rodents. However, for clinical applicability, it is critical to obtain proof of the concept regarding the efficacy of grafted human iPSC-NS/PCs (hiPSC-NS/PCs) for the repair of spinal cord injury (SCI) in a non-human primate model. This study used a pre-evaluated "safe" hiPSC-NS/PC clone and an adult common marmoset (Callithrix jacchus) model of contusive SCI. SCI was induced at the fifth cervical level (C5), followed by transplantation of hiPSC-NS/PCs at 9 days after injury. Behavioral analyses were performed from the time of the initial injury until 12 weeks after SCI. Grafted hiPSC-NS/PCs survived and differentiated into all three neural lineages. Furthermore, transplantation of hiPSC-NS/PCs enhanced axonal sparing/regrowth and angiogenesis, and prevented the demyelination after SCI compared with that in vehicle control animals. Notably, no tumor formation occurred for at least 12 weeks after transplantation. Quantitative RT-PCR showed that mRNA expression levels of human neurotrophic factors were significantly higher in cultured hiPSC-NS/PCs than in human dermal fibroblasts (hDFs). Finally, behavioral tests showed that hiPSC-NS/PCs promoted functional recovery after SCI in the common marmoset. Taken together, these results indicate that pre-evaluated safe hiPSC-NS/PCs are a potential source of cells for the treatment of SCI in the clinic.
authors.affiliation: Department of Orthopedic Surgery, School of Medicine, Keio University, Tokyo, Japan.
authors.forename: Yoshiomi
authors.initials: Y
authors.lastname: Kobayashi
authors.forename: Yohei
authors.initials: Y
authors.lastname: Okada
authors.forename: Go
authors.initials: G
authors.lastname: Itakura
authors.forename: Hiroki
authors.initials: H
authors.lastname: Iwai
authors.forename: Soraya
authors.initials: S
authors.lastname: Nishimura
authors.forename: Akimasa
authors.initials: A
authors.lastname: Yasuda
authors.forename: Satoshi
authors.initials: S
authors.lastname: Nori
authors.forename: Keigo
authors.initials: K
authors.lastname: Hikishima
authors.forename: Tsunehiko
authors.initials: T
authors.lastname: Konomi
authors.forename: Kanehiro
authors.initials: K
authors.lastname: Fujiyoshi
authors.forename: Osahiko
authors.initials: O
authors.lastname: Tsuji
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Toyama
authors.forename: Shinya
authors.initials: S
authors.lastname: Yamanaka
authors.forename: Masaya
authors.initials: M
authors.lastname: Nakamura
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Okano
mesh_terms: D000818:Animals; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism; D002144:Callithrix; D002454:Cell Differentiation; D002470:Cell Survival; D002471:Cell Transformation, Neoplastic / Q000473:pathology*; D002478:Cells, Cultured; D002921:Cicatrix / Q000473:pathology; D003711:Demyelinating Diseases / Q000517:prevention & control; D005260:Female; D018737:Hand Strength; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000378:metabolism / Q000502:physiology / Q000637:transplantation*; D008124:Locomotion; D017628:Microglia / Q000502:physiology; D009046:Motor Neurons / Q000378:metabolism / Q000473:pathology; D018919:Neovascularization, Physiologic; D009414:Nerve Growth Factors / Q000378:metabolism; D009416:Nerve Regeneration; D058953:Neural Stem Cells / Q000378:metabolism / Q000502:physiology / Q000637:transplantation*; D020127:Recovery of Function; D013116:Spinal Cord / Q000098:blood supply / Q000473:pathology / Q000503:physiopathology; D013119:Spinal Cord Injuries / Q000473:pathology / Q000628:therapy*; D033581:Stem Cell Transplantation / Q000009:adverse effects
chemical_list: D009414:Nerve Growth Factors; D015740:Calcitonin Gene-Related Peptide