Abstract
The success of cell transplantation therapy for ischemic stroke is hindered by the low cell survival rate in poststroke brain, due in part to high free radical production and ensuing oxidative stress. We have developed redox nanoparticles to eliminate reactive oxygen species. In this study, we tested the protective efficacy of these redox nanoparticles in cell culture and a mouse model of ischemic stroke. Induced human dental pulp stem cells were subjected to oxygen–glucose deprivation and reoxygenation to recapitulate ischemia and reperfusion in the penumbra surrounding a cerebral infarct. Cell viability using WST-8 assay, apoptosis using TUNEL, free radicals using MitoSOX, and inflammatory cytokines using ELISA kit were measured in the presence and absence of redox nanoparticles after oxygen–glucose deprivation and reoxygenation. The scavenging activity of redox nanoparticles against reactive oxygen species was detected by electron spin resonance. Moreover, induced cells were transplanted intracerebrally into to the distal middle cerebral artery occlusion model with and without redox nanoparticles, and the survival rate measured. Cell viability was enhanced, while apoptosis, free radical generation, and inflammatory cytokine expression levels were reduced in cultures with redox nanoparticles. Further, reduced redox nanoparticles were detected in the cytoplasm, indicating free radical scavenging. Addition of redox nanoparticles also improved the survival rate of transplanted cells after 6 weeks in vivo. These redox nanoparticles may increase the applicability and success of induced stem cell therapy for ischemic stroke patents by promoting long-term survival.
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Acknowledgements
We thank Yoshiko Tsukada and Makiko Miyakawa from the Graduate School of Comprehensive Human Sciences, University of Tsukuba, for their technical support.
Funding
This work was supported by a Grant-in-Aid for Scientific Research (C) to YM. (no. 19K09450), Scientific Research (B), and JST FOREST Program, Grant Number JPMJFR2112 to AM (no. 20H03787). The design and preparation of RNPs was supported by a JSPS KAKENHI Grant-in-Aid for Scientific Research (S) under Grant Number 25220203 and a Grant-in-Aid for Specially promoted Research under Grant Number 19H05458 to YN.
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Koji Hirata, Aiki Marushima, Yukio Nagasaki, Hiroshi Ishikawa, Hideaki Matsumura, Arnela Mujagić, Aki Hirayama, Junko Toyomura, Akihiro Ohyama, Hiroki Bukawa, and Yuji Matsumaru are inventors of the redox nanoparticles used in this research and are listed on registered or pending patents. Aiki Marushima is the representative director and shareholder of CrestecBio Inc. and Yukio Nagasaki is an advisory and shareholder of CrestecBio Inc., which holds registered or pending patents on redox nanoparticles. The other authors have no conflicts of interest to declare.
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Hirata, K., Marushima, A., Nagasaki, Y. et al. Efficacy of redox nanoparticles for improving survival of transplanted cells in a mouse model of ischemic stroke. Human Cell 36, 1703–1715 (2023). https://doi.org/10.1007/s13577-023-00940-4
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DOI: https://doi.org/10.1007/s13577-023-00940-4