Treatment with a Gamma-Secretase Inhibitor Promotes Functional Recovery in Human iPSC- Derived Transplants for Chronic Spinal Cord Injury

摘要

class="head no_bottom_margin" id="sec1title">IntroductionSpinal cord injury (SCI) is a catastrophic trauma that causes permanent paralysis, sensory disturbances, neuropathic pain, and bowel-bladder dysfunction (). Demographically, most patients with SCI are in the chronic phase, and therapeutic development becomes imperative in this stage. Numerous studies have demonstrated the efficacy of transplanting neural stem/progenitor cells (NS/PCs) for the treatment of SCI, but the optimal time window for transplantation is regarded as the subacute phase after injury (, , , ). Treatment of chronic SCI is difficult due to phase-dependent changes in the intramedullary environment, such as glial scar and cavity formation. Unfortunately, reports showing favorable outcomes of targeting the chronic phase have been limited. In fact, several studies have failed to identify significant motor function recovery after cell transplantation in chronically injured spinal cords (, , ). Only a few reports have shed light on this challenging situation and have shown that neural precursor cell transplantation combined with chondroitinase ABC treatment, which promotes the degradation of chondroitin sulfate proteoglycans, improves locomotor function recovery in chronic SCI (, ). However, these procedures are technically demanding and are not clinically relevant, due to the necessity for implantation of an intrathecal catheter prior to cell transplantation.We previously reported that NS/PCs derived from human induced pluripotent stem cells (hiPSC-NS/PCs) treated with a gamma-secretase inhibitor (GSI) (Notch signal inhibitor) exhibit a reduced proportion of dividing cells and increased neuronal maturation in vitro. Transplantation of these cells leads to robust axonal regrowth and promotes motor function recovery in rodents with subacute SCI (). These results prompted the use of GSI treatment for chronic SCI because graft cell-derived neuronal maturation plays beneficial roles in functional improvement by reconstructing neural circuits in the injured spinal cord, even when transplantation is performed in the chronic stage (, ). If GSI-treated NS/PCs exert their ability to extend neuronal axons against the harsh chronic environment and integrate with host tissue through functional synapses, significant effects that could lead to locomotor recovery in the case of transplantation are expected.Therefore, the purpose of the present study was to evaluate the efficacy of GSI-treated hiPSC-NS/PC transplantation in the chronic phase of SCI. Because GSI treatment takes only 1 day to achieve neuronal induction, this methodology has the potential to become an efficient and useful tool for cell transplantation therapy in SCI.