Design and Evaluation of an In Vitro Mild Traumatic Brain Injury Modeling System Using 3D Printed Mini Impact Device on the 3D Cultured Human iPSC Derived Neural Progenitor Cells.
Design and Evaluation of an In Vitro Mild Traumatic Brain Injury Modeling System Using 3D Printed Mini Impact Device on the 3D Cultured Human iPSC Derived Neural Progenitor Cells.
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体外轻度创伤性脑损伤建模系统的设计和评估，该系统使用3D打印的微型冲击装置对3D培养的人iPSC衍生的神经祖细胞进行。
DOI：
10.1002/adhm.202100180
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发表时间：
2021-06
影响因子：
10
通讯作者：
Duan B
中科院分区：
文献类型：
--
作者：
Shi W;Dong P;Kuss MA;Gu L;Kievit F;Kim HJ;Duan B
创伤性脑损伤（TBI）是一种严重的公共卫生负担，影响着全球数百万人。尽管在理解脑生物力学损伤背后的神经病理学变化方面取得了重大进展，但有前途的临床前治疗方法很少在临床试验中转化为成功的结果。原因之一是临床前模型主要基于小动物，与人类相比，小动物在中枢神经系统（CNS）中具有生理和功能差异。迫切需要一种更人性化的模型来开发新的治疗策略，并解决临床前研究和患者医学治疗之间的差距。在这份报告中，我们开发了一种基于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，以评估3D打印的迷你重量跌落冲击装置的单次和重复mTBI的后果。通过计算机模拟，了解重力下落冲击力对NPC分化神经球的单一和累积效应。实验结果表明，反复（10次）轻度撞击后，神经球显示反应性星形胶质细胞增生和胶质瘢痕形成，而在一次或两次轻度撞击后，没有发现明显的星形胶质细胞活化。进一步开发了人小胶质细胞与神经球的3D共培养模型。结果发现，两次轻度撞击后，星形胶质细胞反应增强，这可能是由于小胶质细胞活化后的慢性神经炎症所致，其特征是促炎细胞因子和趋化因子的持续增加。我们的体外mTBI建模系统可以概括脑撞击损伤的几个特征，并可能作为一个平台，以更好地了解疾病机制，确定新的目标，并筛选候选药物。
Traumatic brain injury (TBI) is a severe public health burden affecting millions of people worldwide. Despite significant progress in understanding the neuro-pathological changes behind the biomechanical injury to the brain, promising preclinical therapeutics have seldom been translated into successful outcomes in clinical trials. One of the reasons is that preclinical models are mainly based on small animals, which have physiological and functional differences in the central nervous system (CNS) compared to humans. A more human relevant model is urgently required to develop new therapeutic strategies and to address the gap between preclinical studies and patient medical treatments. In this report, we have developed an in vitro mild TBI (mTBI) modeling system based on 3D cultured human induced pluripotent stem cells (iPSC) derived neural progenitor cells (iPSC-NPCs) to evaluate the consequence of single and repetitive mTBI by a 3D printed mini weight-drop impact device. Computational simulation was performed to understand the single and cumulative effects of weight-drop impact force on the NPC differentiated neurospheres. Experimental results demonstrated that the neurospheres showed reactive astrogliosis and glial scar formation after repetitive (10 hits) mild impacts, while no obvious astrocyte activation was found after one or two mild impacts. A 3D co-culture model of human microglia cells with the neurosphere was further developed. It was found that astrocyte response was promoted even after two mild impacts, which might be caused by the chronic neuroinflammation after microglia activation, characterized by the sustained increase of pro-inflammatory cytokines and chemokines. Our in vitro mTBI modeling system could recapitulate several hallmarks of the brain impact injury and might serve as a platform to better understand the disease mechanism, identify novel targets, and screen drug candidates.
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DOI：
10.1097/nen.0000000000000115
发表时间：
2014-10
影响因子：
3.2
作者：
Bolton AN;Saatman KE
通讯作者：
Saatman KE
影响因子：
5.3
作者：
Burda JE;Bernstein AM;Sofroniew MV
通讯作者：
Sofroniew MV
影响因子：
16.6
作者：
Batiuk, Mykhailo Y.;Martirosyan, Araks;Holt, Matthew G.
通讯作者：
Holt, Matthew G.
影响因子：
1.9
作者：
Brasiliano Ferreira, Luiz Carlos;Regner, Andrea;Simon, Daniel
通讯作者：
Simon, Daniel
影响因子：
6.9
作者：
Chodobski A;Zink BJ;Szmydynger-Chodobska J
通讯作者：
Szmydynger-Chodobska J