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

Toshiki Okubo,Narihito Nagoshi,Munehisa Shinozaki,Morio Matsumoto,Osahiko Tsuji,Masaya Nakamura,Hideyuki Okano,Shinsuke Shibata,Jun Kohyama,Yoshitaka Kase

doi:10.1016/j.stemcr.2018.10.022

Toshiki Okubo, Narihito Nagoshi + Show 8 more

Open Access

https://doi.org/10.1016/j.stemcr.2018.10.022

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Abstract

SummaryTreatment 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.

Highlights

Spinal cord injury (SCI) is a catastrophic trauma that causes permanent paralysis, sensory disturbances, neuropathic pain, and bowel-bladder dysfunction (Mothe and Tator, 2013)
gamma-secretase inhibitor (GSI)-Treated hiPSC-neural stem/progenitor cells (NS/PCs) Survive and Differentiate into Mature Neurons Following Transplantation in the Chronic Phase of SCI Contusive moderate SCI was induced at the Th10 level in spinal cords of adult female non-obese diabetic (NOD)-severe combined immunodeficiency (SCID) (NOD/ShiJicscidJcl; mice) using an IH impactor with a stainless steel-tipped impactor
To monitor the survival and growth of the transplanted cells in the injured mouse spinal cord, hiPSC-not significant (NS)/PCs were lentivirally transduced with ffLuc, a fusion protein between Venus fluorescent protein and firefly luciferase (Hara-Miyauchi et al, 2012), which allowed transplanted cells to be identified by bioluminescent luciferase signals and fluorescent Venus signals

Summary

Introduction

Spinal cord injury (SCI) is a catastrophic trauma that causes permanent paralysis, sensory disturbances, neuropathic pain, and bowel-bladder dysfunction (Mothe and Tator, 2013). 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 (Karimi-Abdolrezaee et al, 2010; Suzuki et al, 2017). These procedures are technically demanding and are not clinically relevant, due to the necessity for implantation of an intrathecal catheter prior to cell transplantation

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