April 5, 2022
Keio University School of Medicine
Japan Agency for Medical Research and Development
A research group from the Keio University School of Medicine, Department of Physiology, led by Assistant Professor Yoshitaka Kase, Gekka Sato (a student in the Doctoral Programs at the Graduate School of Medicine), Yushi Okano (a student at the School of Medicine), and Professor Hideyuki Okano, has elucidated a new signaling pathway that promotes neurite outgrowth in nerve cells (neurons) derived from human iPS cells. They also discovered that RK-682, a compound produced by the antibiotic-producing bacteria of the *Streptomyces* genus, promotes this newly discovered signaling pathway and extends the neurites of human neurons.
While research on the mechanisms of neurite outgrowth has traditionally been conducted on non-human neurons (such as those from mice, rats, and zebrafish), this study focused on human neurons derived from human iPS cells, with an eye toward future applications in regenerative therapy for chronic spinal cord injury. In regenerative medicine for spinal cord injury using transplanted human iPS cell-derived neural stem/progenitor cells, a critical point for regeneration is how well the transplanted cells, after differentiating into neurons, can extend their neurites to the host's neurons.
The research revealed that the GADD45G/p38 MAPK/CDC25B signaling pathway acts on CRMP2, an enzyme that promotes the polymerization of microtubules which form the cytoskeleton of neurites, thereby extending them. The GADD45G gene was known to play an important role in the evolution of the human cerebrum, but its function in human neurons was unknown. This study has now elucidated its role in neurons for the first time. Furthermore, it was found that RK-682 extends neurites by activating the p38 MAPK/CDC25B part of this signaling pathway.
Furthermore, the group has previously demonstrated at the mouse level that chronic spinal cord injury can be treated by transplanting human iPS cell-derived neural stem/progenitor cells into the injury site after treating them with the γ-secretase inhibitor DAPT. They have now discovered that among γ-secretase inhibitors, Compound 34 exhibits an equivalent effect at one-tenth the dose of DAPT.
The results of this research were published in the international scientific journal "iScience" (Cell Press) on April 4, 2022 (U.S. Eastern Standard Time). A patent application has also been filed to apply these discoveries to transplantation therapy for chronic spinal cord injury using human iPS cell-derived neural stem/progenitor cells. This research is significant both biologically, as it is the first to elucidate the role in neurons of GADD45G, a gene important for the evolution of the human cerebrum, and as translational research, connecting findings from basic research to actual clinical applications for treating chronic spinal cord injury.
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