Brain organoid maturation and implantation integration based on electrical signals input.

Xiao-Hong Li, Nan Hu, Zhe-Han Chang, Jian-Xin Shi, Xiu Fan, Meng-Meng Chen, Shuang-Qing Bao, Chong Chen, Jia-Chen Zuo, Xiao-Wang Zhang, Jing-Jing Wang, Dong Ming
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Abstract

Introduction: Brain organoids are believed to be able to regenerate impaired neural circuits and reinstate brain functionality. The neuronal activity of organoids is considered a crucial factor for restoring host function after implantation. However, the optimal stage of brain organoid post-transplantation has not yet been established. External electrical signal plays a crucial role in the physiology and development of a majority of human tissues. However, whether electrical input modulates the development of brain organoids, making them ideal transplant donors, is elusive.

Methods: Bioelectricity was input into cortical organoids by electrical stimulation (ES) with a multi-electrode array (MEA) to obtain a better-transplanted candidate with better viability and maturity, realizing structural-functional integration with the host brain.

Results: We found that electrical stimulation facilitated the differentiation and maturation of organoids, displaying well-defined cortical plates and robust functional electrophysiology, which was probably mediated via the pathway of calcium-calmodulin (CaM) dependent protein kinase II (CAMK II)-protein kinase A (PKA)-cyclic-AMP response binding protein (pCREB). The ES-pretreated D40 organoids displayed superior cell viability and higher cell maturity, and were selected to transplant into the damaged primary sensory cortex (S1) of host. The enhanced maturation was exhibited within grafts after transplantation, including synapses and complex functional activities. Moreover, structural-functional integration between grafts and host was observed, conducive to strengthening functional connectivity and restoring the function of the host injury.

Conclusion: Our findings supported that electrical stimulation could promote the development of cortical organoids. ES-pretreated organoids were better-transplanted donors for strengthening connectivity between grafts and host. Our work presented a new physical approach to regulating organoids, potentially providing a novel translational strategy for functional recovery after brain injury. In the future, the development of 3D flexible electrodes is anticipated to overcome the drawbacks of 2D planar MEA, promisingly achieving multimodal stimulation and long-term recordings of brain organoids.

基于电信号输入的大脑类器官成熟和植入整合。
简介脑组织器官被认为能够再生受损的神经回路并恢复大脑功能。有机体的神经元活性被认为是植入后恢复宿主功能的关键因素。然而,大脑类器官移植后的最佳阶段尚未确定。外部电信号在大多数人体组织的生理和发育过程中起着至关重要的作用。然而,电输入是否能调节脑组织器官的发育,使其成为理想的移植供体,目前尚无定论:方法:通过多电极阵列(MEA)电刺激(ES)将生物电输入大脑皮质类器官,以获得存活率和成熟度更高的移植候选器官,实现与宿主大脑在结构和功能上的整合:结果:我们发现电刺激促进了器官组织的分化和成熟,使其显示出清晰的皮质板块和强大的功能电生理学,这可能是通过钙-钙调蛋白(CaM)依赖性蛋白激酶II(CAMK II)-蛋白激酶A(PKA)-环-AMP反应结合蛋白(pCREB)途径介导的。经ES预处理的D40器官组织显示出卓越的细胞活力和更高的细胞成熟度,并被选中移植到宿主受损的初级感觉皮层(S1)中。移植后,移植物内部表现出更高的成熟度,包括突触和复杂的功能活动。此外,还观察到移植物与宿主之间的结构-功能整合,这有利于加强功能连接和恢复宿主损伤的功能:我们的研究结果表明,电刺激可促进大脑皮层有机体的发育。结论:我们的研究结果表明,电刺激可促进大脑皮层器官组织的发育,ES预处理的器官组织是更好的移植供体,有利于加强移植物与宿主之间的连接。我们的工作提出了一种新的物理方法来调节器官组织,有可能为脑损伤后的功能恢复提供一种新的转化策略。未来,三维柔性电极的开发有望克服二维平面MEA的缺点,有望实现对脑组织器官的多模式刺激和长期记录。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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