Department of Mechanical Engineering, Korea Advanced Institute of Science and Technology, 291, Daehak-ro, Daejeon, 34141, Republic of Korea.
Sci Rep. 2024 Nov 7;14(1):27032. doi: 10.1038/s41598-024-78522-z.
Stroke remains one of the major health challenges due to its high rates of mortality and long-term disability, necessitating the development of effective therapeutic treatment. This study aims to explore the neuroprotective effects of hypoxic postconditioning (HPC) using a cell-based 3D cortical ischemic-hypoxic injury model. Our model employs murine cells to investigate HPC-induced modulation of glial cell reactivity and intercommunication post-oxygen-glucose deprivation-reoxygenation (OGD-R) injury. We found that a single HPC session (1HPC) provided the most significant neuroprotection post-OGD-R compared to multiple intermittent hypoxic treatments, evidenced by improved spheroidal structure, enhanced cell survival and reduced apoptosis, optimal modulation of neuronal phenotypes, dampened ischemic responses, and augmented neurite outgrowth of spheroids. Furthermore, 1HPC suppressed both pro-inflammatory A1 and anti-inflammatory A2 astrocyte phenotypes despite the induction of astrocyte activation while reducing microglial activation with inhibited M1 and M2 reactive states. This was accompanied by a decrease in gene expression of the pro-inflammatory cytokines essential to microglia-astrocyte signaling, collectively suggesting a shift of glial cells away from their traditional reactive states for neuroprotection. This study highlights the potential of 1HPC as a novel therapeutic intervention for ischemic injury via the modulation of neuroprotective glial reactivity. Moreover, the 3D cortical ischemic-hypoxic injury model employed here holds enormous potential serving as a disease model to further elucidate the underlying mechanism of HPC, which can also extend to the applications in brain regeneration, drug development, and the modeling of neural diseases.
中风仍然是一个主要的健康挑战，因为其高死亡率和长期残疾率，需要开发有效的治疗方法。本研究旨在使用基于细胞的 3D 皮质缺血缺氧损伤模型，探讨缺氧后处理（HPC）的神经保护作用。我们的模型采用鼠细胞来研究 HPC 诱导的氧葡萄糖剥夺复氧（OGD-R）损伤后神经胶质细胞反应和相互通讯的调节。我们发现，与多次间歇性低氧处理相比，单次 HPC 处理（1HPC）在 OGD-R 后提供了最显著的神经保护作用，表现为球体结构改善、细胞存活率提高和凋亡减少、神经元表型最佳调节、缺血反应减弱以及球体的神经突生长增强。此外，1HPC 抑制了促炎 A1 和抗炎 A2 星形胶质细胞表型，尽管诱导了星形胶质细胞激活，但同时减少了小胶质细胞激活，抑制了 M1 和 M2 反应状态。这伴随着对小胶质细胞-星形胶质细胞信号至关重要的促炎细胞因子的基因表达减少，共同表明胶质细胞从传统的反应状态转移以实现神经保护。这项研究强调了 1HPC 通过调节神经保护胶质细胞反应作为缺血性损伤的一种新的治疗干预的潜力。此外，这里使用的 3D 皮质缺血缺氧损伤模型具有巨大的潜力，可以作为疾病模型来进一步阐明 HPC 的潜在机制，也可以扩展到脑再生、药物开发和神经疾病建模的应用。
