Brain Repair and Intracranial Neurotherapeutics (BRAIN), Biomedical Research Unit, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, CF24 4HQ, UK.
Institute of Psychological Medicine and Clinical Neurosciences, National Institute for Neuroscience and Mental Health Research, Cardiff University, Cardiff, UK.
J Neuroinflammation. 2021 Sep 21;18(1):218. doi: 10.1186/s12974-021-02265-1.
The dentate gyrus exhibits life-long neurogenesis of granule-cell neurons, supporting hippocampal dependent learning and memory. Both temporal lobe epilepsy patients and animal models frequently have hippocampal-dependent learning and memory difficulties and show evidence of reduced neurogenesis. Animal and human temporal lobe epilepsy studies have also shown strong innate immune system activation, which in animal models reduces hippocampal neurogenesis. We sought to determine if and how neuroinflammation signals reduced neurogenesis in the epileptic human hippocampus and its potential reversibility.
We isolated endogenous neural stem cells from surgically resected hippocampal tissue in 15 patients with unilateral hippocampal sclerosis. We examined resultant neurogenesis after growing them either as neurospheres in an ideal environment, in 3D cultures which preserved the inflammatory microenvironment and/or in 2D cultures which mimicked it.
3D human hippocampal cultures largely replicated the cellular composition and inflammatory environment of the epileptic hippocampus. The microenvironment of sclerotic human epileptic hippocampal tissue is strongly anti-neurogenic, with sustained release of the proinflammatory proteins HMGB1 and IL-1β. IL-1β and HMGB1 significantly reduce human hippocampal neurogenesis and blockade of their IL-1R and TLR 2/4 receptors by IL1Ra and Box-A respectively, significantly restores neurogenesis in 2D and 3D culture.
Our results demonstrate a HMGB1 and IL-1β-mediated environmental anti-neurogenic effect in human TLE, identifying both the IL-1R and TLR 2/4 receptors as potential drug targets for restoring human hippocampal neurogenesis in temporal lobe epilepsy.
齿状回具有颗粒细胞神经元的终身神经发生能力，支持海马依赖的学习和记忆。颞叶癫痫患者和动物模型通常都存在海马依赖的学习和记忆困难，并表现出神经发生减少的证据。动物和人类颞叶癫痫研究也显示出强烈的固有免疫系统激活，在动物模型中，这种激活会减少海马神经发生。我们试图确定神经炎症信号是否以及如何减少癫痫患者海马中的神经发生，以及其潜在的可逆性。
我们从 15 名单侧海马硬化患者的手术切除海马组织中分离出内源性神经干细胞。我们将它们在理想环境中培养成神经球，在保留炎症微环境的 3D 培养物中培养，或者在模拟其环境的 2D 培养物中培养，然后检查它们的神经发生情况。
3D 人类海马培养物在很大程度上复制了癫痫海马的细胞组成和炎症环境。硬化性人类癫痫海马组织的微环境具有强烈的抗神经发生作用，持续释放促炎蛋白 HMGB1 和 IL-1β。IL-1β 和 HMGB1 显著减少人类海马神经发生，通过 IL1Ra 和 Box-A 分别阻断其 IL-1R 和 TLR 2/4 受体，可显著恢复 2D 和 3D 培养物中的神经发生。
我们的结果表明，HMGB1 和 IL-1β 在人类 TLE 中具有环境抗神经发生作用，确定了 IL-1R 和 TLR 2/4 受体作为恢复颞叶癫痫患者海马神经发生的潜在药物靶点。
