UCI Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, United States; Center for Advanced Sciences and Technology (CAST), University "G. d'Annunzio" of Chieti-Pescara, Chieti, Italy; Department of Neuroscience, Imaging and Clinical Sciences, University G d'Annunzio of Chieti-Pescara, Chieti, Italy.
UCI Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, United States; Sue and Bill Gross Stem Cell Research Center, University of California, Irvine, CA, United States; Department of Neurobiology and Behavior, University of California, Irvine, CA, United States; Institute for Neurodegenerative Diseases, University of California, San Francisco, CA, United States.
Cell Calcium. 2024 Nov;123:102923. doi: 10.1016/j.ceca.2024.102923. Epub 2024 Jun 13.
The central nervous system (CNS) is constantly surveilled by microglia, highly motile and dynamic cells deputed to act as the first line of immune defense in the brain and spinal cord. Alterations in the homeostasis of the CNS are detected by microglia that respond by extending their processes or - following major injuries - by migrating toward the affected area. Understanding the mechanisms controlling directed cell migration of microglia is crucial to dissect their responses to neuroinflammation and injury. We used a combination of pharmacological and genetic approaches to explore the involvement of calcium (Ca) signaling in the directed migration of human induced pluripotent stem cell (iPSC)-derived microglia challenged with a purinergic stimulus. This approach mimics cues originating from injury of the CNS. Unexpectedly, simultaneous imaging of microglia migration and intracellular Ca changes revealed that this phenomenon does not require Ca signals generated from the endoplasmic reticulum (ER) and store-operated Ca entry (SOCE) pathways. Instead, we find evidence that human microglial chemotaxis to purinergic signals is mediated by cyclic AMP in a Ca-independent manner. These results challenge prevailing notions, with important implications in neurological conditions characterized by perturbation in Ca homeostasis.
中枢神经系统（CNS）不断受到小胶质细胞的监测，小胶质细胞是一种高度活跃和动态的细胞，被派往大脑和脊髓充当第一道免疫防御。小胶质细胞检测到 CNS 内环境平衡的改变，通过延伸其突起来作出反应，或者在受到严重损伤时向受影响的区域迁移。理解控制小胶质细胞定向细胞迁移的机制对于剖析它们对神经炎症和损伤的反应至关重要。我们使用药理学和遗传学方法的组合，探索钙（Ca）信号在人类诱导多能干细胞（iPSC）衍生的小胶质细胞对嘌呤能刺激的定向迁移中的作用。这种方法模拟了源自中枢神经系统损伤的信号。出乎意料的是，同时对小胶质细胞迁移和细胞内 Ca 变化进行成像，揭示了这种现象不需要内质网（ER）和储存操作的 Ca 内流（SOCE）途径产生的 Ca 信号。相反，我们发现有证据表明，人类小胶质细胞对嘌呤能信号的趋化性是通过 cAMP 介导的，且不依赖 Ca。这些结果对普遍存在的观点提出了挑战，对以 Ca 稳态失调为特征的神经疾病具有重要意义。
