Department of Dermatology, School of Medicine and Public Health, University of Wisconsin, 1 S Park Street, Madison, WI, 53715, USA.
Department of Biomedical Engineering, College of Engineering, University of Wisconsin, 1550 Engineering Dr, Madison, WI, 53705, USA.
Lab Chip. 2023 Sep 13;23(18):3945-3960. doi: 10.1039/d3lc00276d.
As a leading cause of mortality and morbidity, stroke constitutes a significant global health burden. Ischemic stroke accounts for 80% of cases and occurs due to an arterial thrombus, which impedes cerebral blood flow and rapidly leads to cell death. As the most abundant cell type within the central nervous system, astrocytes play a critical role within the injured brain. We developed a novel microphysiological platform that permits the induction of spatiotemporally controlled nutrient gradients, allowing us to study astrocytic response during and after transient nutrient deprivation. Within 24 h of inducing starvation in the platform, nutrient deprivation led to multiple changes in astrocyte response, from metabolic perturbations to gene expression changes, and cell viability. Furthermore, we observed that nutrient restoration did not reverse the functional changes in astrocyte metabolism, which mirrors reperfusion injury observed . We also identified alterations in numerous glucose metabolism-associated genes, many of which remained upregulated or downregulated even after restoration of the nutrient supply. Together, these findings suggest that astrocyte activation during and after nutrient starvation induces plastic changes that may underpin persistent stroke-induced functional impairment. Overall, our innovative device presents interesting potential to be used in the development of new therapies to improve tissue repair and even cognitive recovery after stroke.
中风是导致死亡和发病的主要原因之一，也是全球健康的重大负担。缺血性中风占中风病例的 80%，它是由于动脉血栓形成，阻碍了大脑血液流动，导致细胞迅速死亡。作为中枢神经系统中最丰富的细胞类型，星形胶质细胞在受损大脑中起着关键作用。我们开发了一种新的微生理平台，可以诱导时空控制的营养梯度，使我们能够研究短暂营养剥夺期间和之后星形胶质细胞的反应。在平台上诱导饥饿 24 小时内，营养剥夺导致星形胶质细胞反应的多种变化，从代谢紊乱到基因表达变化和细胞活力。此外，我们观察到营养恢复并没有逆转星形胶质细胞代谢的功能变化，这与观察到的再灌注损伤相似。我们还发现许多与葡萄糖代谢相关的基因发生了改变，其中许多基因即使在营养供应恢复后仍保持上调或下调。总之，这些发现表明，营养饥饿期间和之后星形胶质细胞的激活会诱导可能导致持续性中风引起的功能障碍的可塑性变化。总的来说，我们的创新设备具有很大的潜力，可以用于开发新的治疗方法，以改善中风后的组织修复，甚至认知恢复。
