Shibata Reo, Nagoshi Narihito, Kajikawa Keita, Ito Shuhei, Shibata Shinsuke, Shindo Tomoko, Khazaei Mohamad, Nori Satoshi, Kohyama Jun, Fehlings Michael G, Matsumoto Morio, Nakamura Masaya, Okano Hideyuki
Department of Orthopedic Surgery, Keio University School of Medicine, Tokyo, Japan.
Department of Physiology, Keio University School of Medicine, Tokyo, Japan.
J Neurotrauma. 2022 May;39(9-10):667-682. doi: 10.1089/neu.2021.0225.
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.
在脊髓损伤（SCI）急性期进行人诱导多能干细胞衍生的神经干细胞/祖细胞（hiPSC-NS/PC）移植并不有效，因为SCI后立即发生的炎症反应会对移植细胞的存活产生负面影响。因此，我们选择研究强大的趋化因子补体C5a，作为一种营造更有利移植环境的方法。我们假设，通过C5a受体拮抗剂（C5aRA）在SCI后立即抑制炎症反应，将提高hiPSC-NS/PC移植治疗急性期SCI的疗效。在此，我们评估了C5aRA对SCI后急性期炎症反应的影响，观察到几种炎症细胞因子、巨噬细胞、中性粒细胞和凋亡标志物显著减少。接下来，我们将SCI小鼠分为四组：1）仅注射磷酸盐缓冲盐水（PBS）；2）仅注射C5aRA；3）PBS+移植（PBS+TP）；4）C5aRA+移植（C5aRA+TP）。SCI后立即每天注射一次C5aRA或PBS，连续注射4天，然后在第4天将hiPSC-NS/PC或PBS移植到损伤中心。与仅PBS组相比，C5aRA+TP组的功能改善更好。与PBS+TP组相比，C5aRA+TP组的细胞存活率也显著更高。本研究表明，给予C5aRA可抑制SCI急性期的炎症反应，同时提高移植的hiPSC-NS/PC的存活率，并增强运动功能恢复。在急性损伤期，使用C5aRA进行人诱导多能干细胞衍生的神经干细胞/祖细胞移植对SCI患者是一种有前景的治疗方法。
