Department of Mechanical Engineering, Carnegie Mellon University, Pittsburgh, 15213, PA, USA.
Department of Neurosurgery, University of Pittsburgh Medical Center, Pittsburgh, 15213, PA, USA.
Sci Rep. 2023 Aug 19;13(1):13536. doi: 10.1038/s41598-023-40431-y.
The ability to model physiological systems through 3D neural in-vitro systems may enable new treatments for various diseases while lowering the need for challenging animal and human testing. Creating such an environment, and even more impactful, one that mimics human brain tissue under mechanical stimulation, would be extremely useful to study a range of human-specific biological processes and conditions related to brain trauma. One approach is to use human cerebral organoids (hCOs) in-vitro models. hCOs recreate key cytoarchitectural features of the human brain, distinguishing themselves from more traditional 2D cultures and organ-on-a-chip models, as well as in-vivo animal models. Here, we propose a novel approach to emulate mild and moderate traumatic brain injury (TBI) using hCOs that undergo strain rates indicative of TBI. We subjected the hCOs to mild (2 s[Formula: see text]) and moderate (14 s[Formula: see text]) loading conditions, examined the mechanotransduction response, and investigated downstream genomic effects and regulatory pathways. The revealed pathways of note were cell death and metabolic and biosynthetic pathways implicating genes such as CARD9, ENO1, and FOXP3, respectively. Additionally, we show a steeper ascent in calcium signaling as we imposed higher loading conditions on the organoids. The elucidation of neural response to mechanical stimulation in reliable human cerebral organoid models gives insights into a better understanding of TBI in humans.
通过 3D 神经体外系统对生理系统进行建模的能力可能会为各种疾病提供新的治疗方法，同时降低对挑战性动物和人体测试的需求。创建这样的环境，甚至更具影响力的是，创建一个模拟人类脑组织在机械刺激下的环境，对于研究一系列与脑创伤相关的人类特有的生物学过程和条件将非常有用。一种方法是使用人类脑类器官（hCOs）的体外模型。hCOs 重现了人类大脑的关键细胞结构特征，与更传统的 2D 培养和器官芯片模型以及体内动物模型区分开来。在这里，我们提出了一种使用 hCOs 模拟轻度和中度创伤性脑损伤（TBI）的新方法，hCOs 经历的应变速率与 TBI 一致。我们使 hCOs 经受轻度（2 s[Formula: see text]）和中度（14 s[Formula: see text]）加载条件，检查机械转导反应，并研究下游基因组效应和调节途径。值得注意的途径是细胞死亡以及代谢和生物合成途径，分别涉及 CARD9、ENO1 和 FOXP3 等基因。此外，我们还显示，随着对类器官施加更高的加载条件，钙信号的上升幅度更大。在可靠的人类脑类器官模型中阐明神经对机械刺激的反应为更好地理解人类 TBI 提供了线索。
