Journal Article

Pre-Evaluated Safe Human iPSC-Derived Neural Stem Cells Promote Functional Recovery after Spinal Cord Injury in Common Marmoset without Tumorigenicity

Hikishima, Keigo, Tsuji, Osahiko, Yamanaka, Shinya, Nori, Satoshi, Nishimura, Soraya, Yasuda, Akimasa, Okada, Yohei, Kobayashi, Yoshiomi, Iwai, Hiroki, Fujiyoshi, Kanehiro, Nakamura, Masaya, Toyama, Yoshiaki, Itakura, Go, Konomi, Tsunehiko, Okano, Hideyuki

2012

Overview

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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Angiogenesis / Animals / Biology / Bone surgery / Calcitonin Gene-Related Peptide - metabolism / Callithrix / Callithrix jacchus / Cell culture / Cell Differentiation / Cell Survival / Cell Transformation, Neoplastic - pathology / Cells (biology) / Cells, Cultured / Cicatrix - pathology / Cloning / Demyelinating Diseases - prevention & control / Demyelination / Female / Fibroblasts / Gene expression / Hand Strength / Human behavior / Humans / Induced Pluripotent Stem Cells - physiology / Induced Pluripotent Stem Cells - secretion / Induced Pluripotent Stem Cells - transplantation / Injuries / Injury analysis / Laboratory animals / Locomotion / Medicine / Microglia - physiology / Motor Neurons - metabolism / Motor Neurons - pathology / Neovascularization, Physiologic / Nerve Growth Factors - secretion / Nerve Regeneration / Neural stem cells / Neural Stem Cells - physiology / Neural Stem Cells - secretion / Neural Stem Cells - transplantation / Neurotrophic factors / Orthopedics / Physiology / Pluripotency / Polymerase chain reaction / Primates / Proteins / Recovery / Recovery (Medical) / Recovery of Function / Regrowth / RNA / Rodents / Skin / Spinal Cord - blood supply / Spinal Cord - pathology / Spinal Cord - physiopathology / Spinal cord injuries / Spinal Cord Injuries - pathology / Spinal Cord Injuries - therapy / Stem cell transplantation / Stem Cell Transplantation - adverse effects / Stem cells / Transplantation / Tumorigenicity