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
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
复制标题
C5a 受体拮抗剂的施用可提高脊髓损伤急性期人诱导多能干细胞来源的神经干/祖细胞移植的疗效
DOI：
10.1089/neu.2021.0225
复制
发表时间：
2022
影响因子：
4.2
通讯作者：
Okano Hideyuki
中科院分区：
文献类型：
--
作者：
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
在脊髓损伤（SCI）急性期进行人诱导的多能干细胞衍生的神经干细胞/祖细胞（hiPSC-NS/PC）移植是无效的，因为脊髓损伤后立即发生炎症反应，这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化学引诱剂补体C5a作为产生更有利移植环境的方法。我们假设C5a受体拮抗剂（C5aRA）在脊髓损伤后立即抑制炎症反应可以提高hiPSC-NS/PCs移植治疗急性期脊髓损伤的疗效。在这里，我们评估了C5aRA对脊髓损伤后急性期炎症反应的影响，并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的显著减少。接下来，我们将脊髓损伤小鼠分为四组：1)仅用磷酸盐缓冲盐水（PBS）；2)仅C5aRA；3) PBS+移植（PBS+TP）；4) C5aRA+移植（C5aRA+TP）。脊髓损伤后立即注射C5aRA或PBS，每天1次，连续4天，第4天hiPSC-NS/PC移植或PBS到病变中心。C5aRA+TP组较PBS组有更好的功能改善。C5aRA+TP组的细胞存活率也明显高于PBS+TP组。本研究表明，C5aRA可以抑制脊髓损伤急性期的炎症反应，同时提高移植hiPSC-NS/PCs的存活率，并促进运动功能的恢复。人诱导的多能干细胞来源的神经干细胞/祖细胞移植与C5aRA是一个很有前途的治疗脊髓损伤患者急性期。
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.