Administration of C5a Receptor Antagonist Improves the Efficacy of Human Induced Pluripotent Stem Cell-Derived Neural Stem/Progenitor Cell Transplantation in the Acute Phase of Spinal Cord Injury

Reo Shibata, Narihito Nagoshi, Keita Kajikawa, Shuhei Ito, Shinsuke Shibata, Tomoko Shindo, Mohamad Khazaei, Satoshi Nori, Jun Kohyama, Michael G. Fehlings, Morio Matsumoto, Masaya Nakamura, Hideyuki Okano

Research output: Contribution to journalArticlepeer-review

Abstract

Human-induced pluripotent stem cell-derived neural stem/progenitor cell (hiPSC-NS/PC) transplantation during the acute phase of spinal cord injury (SCI) is not effective due to the inflammatory response occurring immediately after SCI, which negatively impacts transplanted cell survival. Therefore, we chose to study the powerful chemoattractant complement C5a as a method to generate a more favorable transplantation environment. We hypothesized that suppression of the inflammatory response immediately after SCI by C5a receptor antagonist (C5aRA) would improve the efficacy of hiPSC-NS/PCs transplantation for acute phase SCI. Here, we evaluated the influence of C5aRA on the inflammatory reaction during the acute phase after SCI, and observed significant reductions in several inflammatory cytokines, macrophages, neutrophils, and apoptotic markers. Next, we divided the SCI mice into four groups: 1) phosphate-buffered saline (PBS) only; 2) C5aRA only; 3) PBS + transplantation (PBS+TP); and 4) C5aRA + transplantation (C5aRA+TP). Immediately after SCI, C5aRA or PBS was injected once a day for 4 consecutive days, followed by hiPSC-NS/PC transplantation or PBS into the lesion epicenter on Day 4. The C5aRA+TP group had better functional improvement compared with the PBS only group. The C5aRA+TP group also had a significantly higher cell survival rate compared with the PBS+TP group. This study demonstrates that administration of C5aRA can suppress the inflammatory response during the acute phase of SCI, while improving the survival rate of transplanted hiPSC-NS/PCs, as well as enhancing motor functional restoration. Human-induced pluripotent stem cell-derived neural stem/progenitor cell transplantation with C5aRA is a promising treatment during the acute injury phase for SCI patients.

Original languageEnglish
Pages (from-to)667-682
Number of pages16
JournalJournal of Neurotrauma
Volume39
Issue number9-10
DOIs
Publication statusPublished - 2022 May
Externally publishedYes

Keywords

  • cell transplantation
  • cytokines
  • immunotherapy
  • induced pluripotent stem cells (iPSCs)
  • spinal cord injury

ASJC Scopus subject areas

  • Clinical Neurology

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