Pre-evaluated safe human iPSC-derived neural stem cells promote functional recovery after spinal cord injury in common marmoset without tumorigenicity

PLoS One. 2012;7(12):e52787. doi: 10.1371/journal.pone.0052787. Epub 2012 Dec 27.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcitonin Gene-Related Peptide / metabolism
  • Callithrix
  • Cell Differentiation
  • Cell Survival
  • Cell Transformation, Neoplastic / pathology*
  • Cells, Cultured
  • Cicatrix / pathology
  • Demyelinating Diseases / prevention & control
  • Female
  • Hand Strength
  • Humans
  • Induced Pluripotent Stem Cells / metabolism
  • Induced Pluripotent Stem Cells / physiology
  • Induced Pluripotent Stem Cells / transplantation*
  • Locomotion
  • Microglia / physiology
  • Motor Neurons / metabolism
  • Motor Neurons / pathology
  • Neovascularization, Physiologic
  • Nerve Growth Factors / metabolism
  • Nerve Regeneration
  • Neural Stem Cells / metabolism
  • Neural Stem Cells / physiology
  • Neural Stem Cells / transplantation*
  • Recovery of Function
  • Spinal Cord / blood supply
  • Spinal Cord / pathology
  • Spinal Cord / physiopathology
  • Spinal Cord Injuries / pathology
  • Spinal Cord Injuries / therapy*
  • Stem Cell Transplantation / adverse effects

Substances

  • Nerve Growth Factors
  • Calcitonin Gene-Related Peptide

Grant support

This work was supported by grants from Grants-in-Aid for Scientific Research from Japan Society for the Promotion of Science (SPS) and the Ministry of Education, Culture, Sports, Science, and Technology of Japan (MEXT); the Project for Realization of Regenerative Medicine; and Support for Core Institutes for iPS Cell Research from the MEXT; Japan Science and Technology–California Institute for Regenerative Medicine collaborative program; “Funding Program for World-leading Innovative R&D on Science and Technology (FIRST Program); the Kanrinmaru project from Keio University; Research Fellowships for Young Scientists from JSPS; Keio Gijuku Academic Development Funds; by a Grant-in-Aid for the Global COE program from MEXT to Keio University; and by a Grant-in-Aid for Scientific Research on Innovative Areas (Comprehensive Brain Science Net- work) from the Ministry of Education, Science, Sports and Culture of Japan. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.