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
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
Externí odkaz: