Neuronal and Tissue Regeneration Laboratory, Centro de Investigación Príncipe Felipe, 46012 Valencia, Spain.
Neuroplasticity and Regeneration Group, Department Cell Biology, Physiology and Immunology, Institute of Neurosciences, Universitat Autònoma de Barcelona and CIBERNED, 08193 Bellaterra, Spain.
Int J Mol Sci. 2021 May 31;22(11):5966. doi: 10.3390/ijms22115966.
We currently lack effective treatments for the devastating loss of neural function associated with spinal cord injury (SCI). In this study, we evaluated a combination therapy comprising human neural stem cells derived from induced pluripotent stem cells (iPSC-NSC), human mesenchymal stem cells (MSC), and a pH-responsive polyacetal-curcumin nanoconjugate (PA-C) that allows the sustained release of curcumin. In vitro analysis demonstrated that PA-C treatment protected iPSC-NSC from oxidative damage in vitro, while MSC co-culture prevented lipopolysaccharide-induced activation of nuclear factor-κB (NF-κB) in iPSC-NSC. Then, we evaluated the combination of PA-C delivery into the intrathecal space in a rat model of contusive SCI with stem cell transplantation. While we failed to observe significant improvements in locomotor function (BBB scale) in treated animals, histological analysis revealed that PA-C-treated or PA-C and iPSC-NSC + MSC-treated animals displayed significantly smaller scars, while PA-C and iPSC-NSC + MSC treatment induced the preservation of β-III Tubulin-positive axons. iPSC-NSC + MSC transplantation fostered the preservation of motoneurons and myelinated tracts, while PA-C treatment polarized microglia into an anti-inflammatory phenotype. Overall, the combination of stem cell transplantation and PA-C treatment confers higher neuroprotective effects compared to individual treatments.
目前，我们缺乏有效的治疗方法来应对与脊髓损伤（SCI）相关的严重神经功能丧失。在这项研究中，我们评估了一种组合疗法，该疗法由诱导多能干细胞（iPSC-NSC）、人骨髓间充质干细胞（MSC）和一种 pH 响应性聚缩醛-姜黄素纳米复合物（PA-C）组成，允许姜黄素持续释放。体外分析表明，PA-C 处理可保护 iPSC-NSC 免受体外氧化损伤，而 MSC 共培养可防止 LPS 诱导的 iPSC-NSC 中核因子-κB（NF-κB）的激活。然后，我们在 SCI 大鼠模型中评估了将 PA-C 递送至鞘内空间与干细胞移植相结合的效果。虽然我们未观察到治疗动物运动功能（BBB 评分）有明显改善，但组织学分析显示，PA-C 处理或 PA-C 和 iPSC-NSC+MSC 处理的动物瘢痕明显较小，而 PA-C 和 iPSC-NSC+MSC 处理可诱导β-III 微管蛋白阳性轴突的保留。iPSC-NSC+MSC 移植促进运动神经元和有髓神经束的保留，而 PA-C 处理将小胶质细胞极化成抗炎表型。总的来说，与单独治疗相比，干细胞移植和 PA-C 联合治疗可提供更高的神经保护作用。
