Mary & Dick Holland Regenerative Medicine Program, University of Nebraska, Medical Center, Omaha, NE, 68198, USA.
Division of Cardiology, Department of Internal Medicine, University of Nebraska, Medical Center, Omaha, NE, 68198, USA.
Adv Healthc Mater. 2021 Jun;10(12):e2100180. doi: 10.1002/adhm.202100180. Epub 2021 Apr 23.
Despite significant progress in understanding the disease mechanism of traumatic brain injury (TBI), promising preclinical therapeutics have seldom been translated into successful clinical outcomes, partially because the model animals have physiological and functional differences in the central nervous system (CNS) compared to humans. Human relevant models are thus urgently required. Here, an in vitro mild TBI (mTBI) modeling system is reported based on 3D cultured human induced pluripotent stem cells (iPSC) derived neural progenitor cells (iPSC-NPCs) to evaluate consequences of single and repetitive mTBI using a 3D printed mini weight-drop impact device. Computational simulation is performed to understand the single/cumulative effects of weight-drop impact on the NPC differentiated neurospheres. Experimental results reveal that neurospheres show reactive astrogliosis and glial scar formation after repetitive (10 hits) mild impacts, while no astrocyte activation is found after one or two mild impacts. A 3D co-culture model of human microglia cells with neurospheres is further developed. It is found that astrocyte response is promoted even after two mild impacts, possibly caused by the chronic neuroinflammation after microglia activation. The in vitro mTBI modeling system recapitulates several hallmarks of the brain impact injury and might serve as a good platform for future drug screening.
尽管人们在理解创伤性脑损伤（TBI）的发病机制方面取得了重大进展，但有前景的临床前治疗方法很少能转化为成功的临床结果，部分原因是模型动物的中枢神经系统（CNS）与人类存在生理和功能差异。因此，迫切需要人类相关的模型。本文报道了一种基于 3D 培养的人诱导多能干细胞（iPSC）衍生的神经祖细胞（iPSC-NPC）的体外轻度 TBI（mTBI）建模系统，用于使用 3D 打印微型重物跌落冲击装置评估单次和重复 mTBI 的后果。进行了计算模拟，以了解重物跌落冲击对 NPC 分化神经球的单次/累积影响。实验结果表明，神经球在重复（10 次冲击）轻度冲击后表现出反应性星形胶质细胞增生和神经胶质瘢痕形成，而单次或两次轻度冲击后未发现星形胶质细胞激活。进一步开发了人小胶质细胞与神经球的 3D 共培养模型。发现即使在两次轻度冲击后，星形胶质细胞的反应也得到了促进，这可能是小胶质细胞激活后的慢性神经炎症引起的。体外 mTBI 建模系统再现了脑冲击损伤的几个特征，可能成为未来药物筛选的良好平台。
