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.

Cell transplantation therapies for spinal cord injury focusing on induced pluripotent stem cells

“…hiPS-neurospheres transplantation enhanced axonal regrowth, myelination and angiogenesis, thereby promoting functional recovery after SCI. It was noteworthy that there was no tumor formation at least for 12 weeks after transplantation [36]. Taken together, pre-evaluated safe hiPSC-derived neurospheres could be a potential cell source for SCI treatment in clinic.…”

Preclinical Studies for Induced Pluripotent Stem Cell-based Therapeutics

“…Human oligodendrocyte progenitors generated from iPSCs mitigated symptoms in a rat model of lysolecithin-induced demyelinated optic chiasm (22). Neural progenitor cells derived from murine or human iPSCs promoted functional and electrophysiological recovery after grafting into the injured spinal cord of rodents and common marmosets, respectively (23,24). Mixed results have been obtained when either rodent or human iPSC-derived progenitor cells have been transplanted into stroke-damaged mouse or rat brains.…”

Stem cells: A time to heal

“…However, many researchers are striving to make them safer. For example, Okano's group studied the impact of immature neural cells -derived from a human iPS clone known not to form tumours -on a primate model of spinal cord injury; the results showed maturing neural cells of several types and no evidence of tumours 5 . In July, the Japanese Ministry of Health, Labour and Welfare approved the first clinical trial using iPS cells.…”