Injury and Treatment of a Human Spinal Cord Organoid

Damage of the spinal cord, which can lead to irreversible paralysis and loss of sensory function, is among the most devastating injuries suffered by humans. A significant effort has been made over the past few decades to find potential therapies to treat spinal cord injury (SCI), an objective that faces the challenge of central nervous system regeneration. Experimental access to human spinal cord tissue is therefore a critical need for discovery of SCI therapies and thus availability of the organ mimics known as organoids offers great potential. Research on spinal cord organoids has been sparse and only very recently enabled by the discovery of the necessary human progenitor cells derived from pluripotent stem cells. We report here on a human organoid model to simulate SCI in vitro and test the potential of novel therapies. We found that the model, involving injury of the organoid with a sharp scalpel, reveals immediate neuronal death and subsequently generates the characteristic glial scar observed after injury with its biological markers. Exposure of the injured organoid to a recently discovered pre-clinical therapy for SCI avoids formation of the scar and promotes axon regeneration in the area of the lesion. Furthermore, in the absence of injury we directly observed the activation of the developmental program to extend axons by the tested therapy, which contains bioactive nanofibers with intense supramolecular motion. The model developed here could accelerate discovery of therapeutic strategies to treat the broad spectrum of spinal cord injuries. Comparative gene expression profiling analysis of single cell RNA-seq data for human spinal cord organoids at two stages (20 weeks and 28 weeks in culture).

脊髓损伤可导致不可逆的瘫痪与感觉功能丧失，是人类所遭受的最具破坏性的损伤之一。过去数十年来，科研人员已投入大量精力探索治疗脊髓损伤（spinal cord injury, SCI）的潜在疗法，但这一目标面临着中枢神经系统再生的难题。因此，获取人类脊髓组织用于实验研究，是发现SCI疗法的关键前提；而被称为类器官（organoids）的器官模拟物的出现，则为该领域带来了巨大潜力。脊髓类器官的相关研究此前较为匮乏，直至近期借助多能干细胞（pluripotent stem cells）来源的必需人类祖细胞的发现，该领域才得以突破。本研究报道了一种可在体外模拟SCI的人类类器官模型，并用于测试新型疗法的潜力。研究发现，通过锋利手术刀对类器官施加损伤的该模型，可快速引发神经元死亡，并随后形成损伤后典型的胶质瘢痕，且该瘢痕带有对应的生物标志物。将受损类器官暴露于新近发现的SCI临床前疗法中，可抑制瘢痕形成，并促进损伤区域的轴突再生。此外，在未施加损伤的情况下，我们直接观察到该受试疗法可激活轴突延伸的发育程序；该疗法含有具备强烈超分子运动活性的生物活性纳米纤维。本研究构建的模型，可加速针对各类脊髓损伤的治疗策略的研发进程。本研究对培养20周和28周两个阶段的人类脊髓类器官的单细胞RNA测序（single cell RNA-seq）数据进行了比较基因表达谱分析。