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

ABSTRACT: Treatment involving regenerative medicine for chronic spinal cord injury (SCI) is difficult due to phase-dependent changes in the intraspinal environment. We previously reported that treatment with a gamma-secretase inhibitor (GSI), which inhibits Notch signaling, promotes the differentiation into mature neurons in human induced pluripotent stem cell-derived neural stem/progenitor cell (hiPSC-NS/PC) transplantation for subacute SCI. Here, we evaluated the efficacy of GSI-treated hiPSC-NS/PC transplantation in treating chronic SCI, which resulted in significantly enhanced axonal regrowth, remyelination, inhibitory synapse formation with the host neural circuitry, and reticulo spinal tract fiber formation. Interestingly, inhibiting Notch signaling with GSI caused phosphorylation of p38 MAPK, which is a key molecule required to promote axonal regeneration. These favorable outcomes contributed to motor function improvement. Therefore, treating cells with GSI provides a beneficial effect after transplantation, even in the chronic phase following SCI.

SUBMITTER: Okubo T

PROVIDER: S-EPMC6294244 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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

Okubo Toshiki T Nagoshi Narihito N Kohyama Jun J Tsuji Osahiko O Shinozaki Munehisa M Shibata Shinsuke S Kase Yoshitaka Y Matsumoto Morio M Nakamura Masaya M Okano Hideyuki H

Stem cell reports 20181129 6

Treatment involving regenerative medicine for chronic spinal cord injury (SCI) is difficult due to phase-dependent changes in the intraspinal environment. We previously reported that treatment with a gamma-secretase inhibitor (GSI), which inhibits Notch signaling, promotes the differentiation into mature neurons in human induced pluripotent stem cell-derived neural stem/progenitor cell (hiPSC-NS/PC) transplantation for subacute SCI. Here, we evaluated the efficacy of GSI-treated hiPSC-NS/PC tran ...[more]

PMID: 30503258

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Project description:Functional recovery after spinal cord injury (SCI) often proves difficult as physical and mental barriers bar survivors from enacting their designated rehabilitation programs. We recently demonstrated that adult mice administered gabapentinoids, clinically approved drugs prescribed to mitigate chronic neuropathic pain, recovered upper extremity function following cervical SCI. Given that rehabilitative training enhances neuronal plasticity and promotes motor recovery, we hypothesized that the combination of an aerobic-based rehabilitation regimen like treadmill training with gabapentin (GBP) administration will maximize recovery in SCI mice by strengthening synaptic connections along the sensorimotor axis. Whereas mice administered GBP recovered forelimb functions over the course of weeks and months following SCI, no additive forelimb recovery as the result of voluntary treadmill training was noted in these mice. To our surprise, we also failed to find an additive effect in mice administered vehicle. As motivation is crucial in rehabilitation interventions, we scored active engagement toward the rehabilitation protocol and found that mice administered GBP were consistently participating in the rehabilitation program. In contrast, mice administered vehicle exhibited a steep decline in participation, especially at chronic time points. Whereas neuroinflammatory gene expression profiles were comparable between experimental conditions, we discovered that mice administered GBP had increased hippocampal neurogenesis and exhibited less anxiety-like behavior after SCI. We also found that an external, social motivator effectively rescues participation in mice administered vehicle and promotes forelimb recovery after chronic SCI. Thus, not only does a clinically relevant treatment strategy preclude the deterioration of mental health after chronic SCI, but group intervention strategies may prove to be physically and emotionally beneficial for SCI individuals.

Dataset Information

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

Publications

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

Similar Datasets

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