Treatment with a Gamma-Secretase Inhibitor Promotes Functional Recovery in Human iPSC- Derived Transplants for Chronic Spinal Cord Injury
Autor: | Osahiko Tsuji, Morio Matsumoto, Toshiki Okubo, Masaya Nakamura, Jun Kohyama, Narihito Nagoshi, Shinsuke Shibata, Munehisa Shinozaki, Hideyuki Okano, Yoshitaka Kase |
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Jazyk: | angličtina |
Rok vydání: | 2018 |
Předmět: |
0301 basic medicine
iPS cell p38 Mitogen-Activated Protein Kinases Biochemistry Mice Neural Stem Cells chronic spinal cord injury GABAergic Neurons Phosphorylation Induced pluripotent stem cell Spinal cord injury lcsh:QH301-705.5 Notch signaling lcsh:R5-920 Receptors Notch motor function Cell Differentiation medicine.anatomical_structure Spinal Cord Female lcsh:Medicine (General) Signal Transduction Cell Survival Induced Pluripotent Stem Cells Neuronal Outgrowth Notch signaling pathway regenerative medicine p38 MAPK Motor Activity Biology Article 03 medical and health sciences Genetics medicine gamma-secretase inhibitor Animals Humans Progenitor cell Remyelination Spinal Cord Injuries Gamma secretase Regeneration (biology) axonal regrowth Recovery of Function Cell Biology medicine.disease Axons Transplantation 030104 developmental biology lcsh:Biology (General) Chronic Disease Synapses Cancer research Amyloid Precursor Protein Secretases Nerve Net transplantation Developmental Biology |
Zdroj: | Stem Cell Reports, Vol 11, Iss 6, Pp 1416-1432 (2018) Stem Cell Reports |
ISSN: | 2213-6711 |
Popis: | Summary 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. Graphical Abstract Highlights • GSI-treated hiPSC-NS/PCs induce regenerative axons and extension of RtST fibers • GSI-treated hiPSC-NS/PCs induce remyelination by host-derived glial cells • GSI causes phosphorylation of p38 MAPK and promotes axonal regeneration • Grafts of GSI-treated hiPSC-NS/PCs provide a beneficial effect in the chronic SCI In this article, Okano and colleagues show that the GSI-treated hiPSC-NS/PCs caused significantly enhanced axonal regrowth, remyelination, inhibitory synapse formation with the host neural circuitry, and reticulo spinal tract fiber formation. 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. |
Databáze: | OpenAIRE |
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