@article{3948ecd0ae60497e815178a714450dbe,
title = "Long-term selective stimulation of transplanted neural stem/progenitor cells for spinal cord injury improves locomotor function",
abstract = "In cell transplantation therapy for spinal cord injury (SCI), grafted human induced pluripotent stem cell-derived neural stem/progenitor cells (hiPSC-NS/PCs) mainly differentiate into neurons, forming synapses in a process similar to neurodevelopment. In the developing nervous system, the activity of immature neurons has an important role in constructing and maintaining new synapses. Thus, we investigate how enhancing the activity of transplanted hiPSC-NS/PCs affects both the transplanted cells themselves and the host tissue. We find that chemogenetic stimulation of hiPSC-derived neural cells enhances cell activity and neuron-to-neuron interactions in vitro. In a rodent model of SCI, consecutive and selective chemogenetic stimulation of transplanted hiPSC-NS/PCs also enhances the expression of synapse-related genes and proteins in surrounding host tissues and prevents atrophy of the injured spinal cord, thereby improving locomotor function. These findings provide a strategy for enhancing activity within the graft to improve the efficacy of cell transplantation therapy for SCI.",
keywords = "DREADD, cell transplantation therapy, chemogenetics, functional recovery, hM3Dq, human iPS cell, neural stem/progenitor cell, selective stimulation, spinal cord injury, synaptic transmission",
author = "Momotaro Kawai and Kent Imaizumi and Mitsuru Ishikawa and Shinsuke Shibata and Munehisa Shinozaki and Takahiro Shibata and Shogo Hashimoto and Takahiro Kitagawa and Kentaro Ago and Keita Kajikawa and Reo Shibata and Yasuhiro Kamata and Junichi Ushiba and Keisuke Koga and Hidemasa Furue and Morio Matsumoto and Masaya Nakamura and Narihito Nagoshi and Hideyuki Okano",
note = "Funding Information: J.U. is one of the founders and the Representative Director of Connect Inc., received a salary from, and holds shares of Connect Inc. M.N. declares a consultancy role with K-Pharma Inc. and research funding from RMic and Hisamitsu. H.O. declares a leadership position at Keio University School of Medicine and is a compensated scientific consultant for San Bio Co. Ltd. and K Pharma Inc. These companies have no relationship with the present study. The other authors declare no competing interest. Funding Information: We are grateful to S. Yamanaka (Kyoto University) for the supply of iPSCs. We thank J. Kohyama, H. Miyoshi, S. Nori, O. Tsuji, and other members of the spinal cord research team in the Department of Orthopedic Surgery/Physiology, Keio University School of Medicine. We also thank T. Harada, K. Yasutake, M. Akizawa, T. Shindo, A. Nakamura, K. Matsumura, and R. Ikeda for their assistance. This work was supported by a grant from the Research Center Network for Realization of Regenerative Medicine by AMED Japan under the grants JP21bm0204001 and JP21bk0104017 to H.O. and M.N.; JP20bm0704046 to S.S.; JP20bm0804023 to M.I.; the Japan Society for the Promotion of Science (JSPS) KAKENHI grants JP20K16133 to K.K. JP20H04043 to H.F. and JP19K18541 to M.K.; AOSpine Research grant AOSJP(R)2019-02 to M.K.; Keio University Grant-in-Aid for Encouragement of Young Medical Scientists to M.K.; Keio University Doctoral Student Grant-in-Aid Program to M.K.; and the General Insurance Association of Japan Medical Research Grant to M.K. The funding sources had no role in the conduct of the study. Conceptualization, M.K. K.I. M.I. S.S. M.S. M.N. N.N. and H.O.; methodology, M.K. K.I. M.I. S.S. M.S. K.K. and H.F.; investigation, M.K. K.I. S.S. M.S. T.S. S.H. T.K. K.A. K.K. R.S. Y.K. K.K. and H.F.; resources, M.K. K.I. M.I. S.S. M.S. M.N. N.N. K.K. and H.F. and H.O.; data curation, M.K. K.I. S.S. M.S. and J.U.; writing ? original draft, M.K. and N.N.; writing ? review & editing, K.I. M.S. J.U. M.M. M.N. K.K. H.F. N.N. and H.O.; supervision, M.K. M.M. N.N. and H.O.; project administration, M.M. N.N. and H.O.; funding acquisition, M.K. M.I. S.S. M.N. N.N. K.K. H.F. and H.O. All authors read and approved the final manuscript. J.U. is one of the founders and the Representative Director of Connect Inc. received a salary from, and holds shares of Connect Inc. M.N. declares a consultancy role with K-Pharma Inc. and research funding from RMic and Hisamitsu. H.O. declares a leadership position at Keio University School of Medicine and is a compensated scientific consultant for San Bio Co. Ltd. and K Pharma Inc. These companies have no relationship with the present study. The other authors declare no competing interest. While citing references scientifically relevant for this work, we also actively worked to promote gender balance in our reference list. Funding Information: We are grateful to S. Yamanaka (Kyoto University) for the supply of iPSCs. We thank J. Kohyama, H. Miyoshi, S. Nori, O. Tsuji, and other members of the spinal cord research team in the Department of Orthopedic Surgery/Physiology, Keio University School of Medicine. We also thank T. Harada, K. Yasutake, M. Akizawa, T. Shindo, A. Nakamura, K. Matsumura, and R. Ikeda for their assistance. This work was supported by a grant from the Research Center Network for Realization of Regenerative Medicine by AMED Japan under the grants JP21bm0204001 and JP21bk0104017 to H.O. and M.N.; JP20bm0704046 to S.S.; JP20bm0804023 to M.I.; the Japan Society for the Promotion of Science (JSPS) KAKENHI grants JP20K16133 to K.K., JP20H04043 to H.F., and JP19K18541 to M.K.; AOSpine Research grant AOSJP(R)2019-02 to M.K.; Keio University Grant-in-Aid for Encouragement of Young Medical Scientists to M.K.; Keio University Doctoral Student Grant-in-Aid Program to M.K.; and the General Insurance Association of Japan Medical Research Grant to M.K. The funding sources had no role in the conduct of the study. Publisher Copyright: {\textcopyright} 2021 The Authors",
year = "2021",
month = nov,
day = "23",
doi = "10.1016/j.celrep.2021.110019",
language = "English",
volume = "37",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "8",
}