@article{02f0828abc2744a5af5d251d387a147d,
title = "Modulation by DREADD reveals the therapeutic effect of human iPSC-derived neuronal activity on functional recovery after spinal cord injury",
abstract = "Transplantation of neural stem/progenitor cells (NS/PCs) derived from human induced pluripotent stem cells (hiPSCs) is considered to be a promising therapy for spinal cord injury (SCI) and will soon be translated to the clinical phase. However, how grafted neuronal activity influences functional recovery has not been fully elucidated. Here, we show the locomotor functional changes caused by inhibiting the neuronal activity of grafted cells using a designer receptor exclusively activated by designer drugs (DREADD). In vitro analyses of inhibitory DREADD (hM4Di)-expressing cells demonstrated the precise inhibition of neuronal activity via administration of clozapine N-oxide. This inhibition led to a significant decrease in locomotor function in SCI mice with cell transplantation, which was exclusively observed following the maturation of grafted neurons. Furthermore, trans-synaptic tracing revealed the integration of graft neurons into the host motor circuitry. These results highlight the significance of engrafting functionally competent neurons by hiPSC-NS/PC transplantation for sufficient recovery from SCI.",
keywords = "DREADD, cell transplantation, human iPS cell, spinal cord injury",
author = "Takahiro Kitagawa and Narihito Nagoshi and Yasuhiro Kamata and Momotaro Kawai and Kentaro Ago and Keita Kajikawa and Reo Shibata and Yuta Sato and Kent Imaizumi and Tomoko Shindo and Munehisa Shinozaki and Jun Kohyama and Shinsuke Shibata and Morio Matsumoto and Masaya Nakamura and Hideyuki Okano",
note = "Funding Information: We appreciate the assistance and instruction provided by Drs. M. Ishikawa, H. Miyoshi, S. Nori, O. Tsuji, K. Kojima, S. Ito, Y. Tanimoto, Y. Hoshino, S. Hashimoto, and T. Shibata, all of whom are members of the spinal cord research team at the Department of Orthopedic Surgery and Physiology, Keio University School of Medicine, Tokyo, Japan. We also appreciate the advice from Dr. K. Tanaka (Department of Psychiatry, Keio University School of Medicine, Tokyo, Japan). We thank Prof. S. Yamanaka (Kyoto University, Kyoto, Japan) for the human iPSC clone and Dr. Y. Miyashita (The University of Tokyo, Tokyo, Japan) for providing a vector containing WGA. We also thank T. Harada, K. Yasutake, M. Akizawa, K. Matsumura, and R. Ikeda for their assistance with the experiments and animal care. This work was supported by the following grants: Research Center Network for Realization of Regenerative Medicine by AMED Japan under grant nos. JP21bm0204001, JP20bm0204001, JP19bm0204001, JP20bk0104017, and JP19bk0104017 to H.O. and M.N. and JP20bm0704046 to S.S. and T.S.; Keio University Grant-in-Aid for Encouragement of Young Medical Scientists (2019 and 2020) to T.K.; and The General Insurance Association of Japan Medical Research Grants 2019 and 2020 to T.K. Funding Information: T.K. designed the project, performed most of the experiments, and interpreted the data. T.K. and N.N. wrote the manuscript. N.N., Y.K., M.K., K.A., K.K., R.S., Y.S., K.I., M.S., J.K., T.S., and S.S. provided experimental support and ideas for the project. M.N. and H.O. supervised the overall project. T.K., N.N., H.O., and M.N. provided financial support. N.N., M.M., M.N., and H.O. edited the manuscript and gave administrative support. All authors read and approved the final manuscript. Publisher Copyright: {\textcopyright} 2021 The Author(s)",
year = "2022",
month = jan,
day = "11",
doi = "10.1016/j.stemcr.2021.12.005",
language = "English",
volume = "17",
pages = "127--142",
journal = "Stem Cell Reports",
issn = "2213-6711",
publisher = "Cell Press",
number = "1",
}