Modulation by DREADD reveals the therapeutic effect of human iPSC-derived neuronal activity on functional recovery after spinal cord injury

Takahiro Kitagawa, Narihito Nagoshi, Yasuhiro Kamata, Momotaro Kawai, Kentaro Ago, Keita Kajikawa, Reo Shibata, Yuta Sato, Kent Imaizumi, Tomoko Shindo, Munehisa Shinozaki, Jun Kohyama, Shinsuke Shibata, Morio Matsumoto, Masaya Nakamura, Hideyuki Okano

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)127-142
Number of pages16
JournalStem cell reports
Volume17
Issue number1
DOIs
Publication statusPublished - 2022 Jan 11

Keywords

  • DREADD
  • cell transplantation
  • human iPS cell
  • spinal cord injury

ASJC Scopus subject areas

  • Biochemistry
  • Genetics
  • Developmental Biology
  • Cell Biology

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