October 15, 2021
Keio University School of Medicine
A research group led by Professor Hideyuki Okano of the Department of Physiology and Professor Masaya Nakamura of the Department of Orthopedic Surgery at the Keio University School of Medicine, in a joint study with Professor Kotaro Takei of the School of Medical Sciences and Graduate School of Medical Life Science at Yokohama City University, has discovered that genetically introducing LOTUS, a Nogo receptor-1 (NgR1) antagonist that promotes neural regeneration, into human iPS cell-derived neural stem/progenitor cells improves the motor function recovery effect of cell transplantation for spinal cord injury.
Although the efficacy of transplanting human iPS cell-derived neural stem/progenitor cells for spinal cord injury has been previously reported, the therapeutic effect has been limited. This is because the environment within the injured spinal cord is harsh for neural regeneration, with the production of NgR1 ligands and other factors inhibiting neuronal axon elongation. Therefore, an improvement in the therapeutic effect has been sought.
Our research group has previously reported through experiments with genetically modified animals that LOTUS, an NgR1 antagonist, has neuroprotective and axon regeneration-promoting effects in the injured spinal cord, contributing to motor function recovery. However, the purification of LOTUS as a protein drug is technically difficult, and its method of administration for spinal cord injury has been a challenge. In this study, we utilized neural stem cells transduced with the LOTUS gene, employing an ex vivo gene therapy approach to verify its therapeutic effect. Specifically, we used a lentiviral vector to genetically introduce LOTUS into human iPS cell-derived neural stem/progenitor cells and transplanted them into subacute spinal cord injury model animals. In the LOTUS gene-transduced neural stem/progenitor cells, axonal elongation was promoted, the inhibition of axonal elongation by NgR1 ligands and apoptosis (cell death) were suppressed, and the expression of neurotrophic factors was increased. Furthermore, upon cell transplantation into the injured spinal cord, the survival rate of the transplanted cells improved, the elongation of nerve fibers from the transplanted cells was promoted, and the number of raphe-spinal tract nerve fibers within the spinal cord increased. As a result, this method showed superior motor function recovery compared to conventional cell transplantation therapy.
This study is the first report of exogenously administering LOTUS to the injured spinal cord by applying ex vivo gene therapy to human iPS cell-derived neural stem/progenitor cell transplantation therapy, and we believe it is a very significant achievement in improving the therapeutic effect of cell transplantation therapy.
The results of this research were published in the online edition of "Stem Cell Reports," the official journal of the International Society for Stem Cell Research (ISSCR), on October 15, 2021 (JST).
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