Ben Dhaou Cyrine, Terrié Elodie, Déliot Nadine, Harnois Thomas, Cousin Laetitia, Arnault Patricia, Constantin Bruno, Moyse Emmanuel, Coronas Valérie
University of Tours, INRAe Centre Val-de-Loire UMR-85, CNRS UMR-1247, Physiologie de la Reproduction et Comportements, Nouzilly, France.
4CS, Laboratory Channels and Connexins in Cancers and Cell Stemness, CNRS UMR 6041, University of Poitiers, Poitiers, France.
Front Cell Neurosci. 2023 Jun 9;17:1200360. doi: 10.3389/fncel.2023.1200360. eCollection 2023.
Neural stem cells (NSCs) persist in specific brain germinative niches and sustain neurogenesis throughout life in adult mammals. In addition to the two major stem cell niches in the subventricular zone and the hippocampal dentate gyrus, the area postrema located in the brainstem has been identified as a neurogenic zone as well. NSCs are regulated by signals from the microenvironment that adjust stem cell response to the needs of the organism. Evidence accumulated over the past decade indicates that Ca channels play pivotal functions in NSC maintenance. In this study, we explored in area postrema NSCs the presence and roles of a subset of Ca channels, the store-operated Ca channels (SOCs) that have the capacity to transduce extracellular signals into Ca signals. Our data show that NSCs derived from the area postrema express TRPC1 and Orai1, known to form SOCs, as well as their activator STIM1. Ca imaging indicated that NSCs exhibit store-operated Ca entries (SOCEs). Pharmacological blockade of SOCEs with SKF-96365, YM-58483 (also known as BTP2) or GSK-7975A resulted in decreased NSC proliferation and self-renewal, indicating a major role for SOCs in maintaining NSC activity within the area postrema. Furthermore, our results show that leptin, an adipose tissue-derived hormone whose ability to control energy homeostasis is dependent on the area postrema, decreased SOCEs and reduced self-renewal of NSCs in the area postrema. As aberrant SOC function has been linked to an increasing number of diseases, including brain disorders, our study opens new perspectives for NSCs in brain pathophysiology.
神经干细胞（NSCs）存在于特定的脑生发微环境中，并在成年哺乳动物的一生中维持神经发生。除了脑室下区和海马齿状回这两个主要的干细胞微环境外，位于脑干的最后区也已被确定为一个神经发生区。神经干细胞受微环境信号的调节，这些信号可根据机体的需求调整干细胞反应。过去十年积累的证据表明，钙通道在神经干细胞的维持中发挥着关键作用。在本研究中，我们在最后区神经干细胞中探索了一类钙通道——储存操纵性钙通道（SOCs）的存在及其作用，这类通道能够将细胞外信号转化为钙信号。我们的数据表明，源自最后区的神经干细胞表达已知可形成SOCs的TRPC1和Orai1，以及它们的激活剂STIM1。钙成像显示神经干细胞表现出储存操纵性钙内流（SOCEs）。用SKF-96365、YM-58483（也称为BTP2）或GSK-7975A对SOCEs进行药理学阻断会导致神经干细胞增殖和自我更新减少，这表明SOCs在维持最后区内神经干细胞活性方面起主要作用。此外，我们的结果表明，瘦素是一种源自脂肪组织的激素，其控制能量稳态的能力依赖于最后区，它会减少最后区神经干细胞的SOCEs并降低其自我更新能力。由于异常的SOC功能与越来越多的疾病（包括脑部疾病）有关，我们的研究为神经干细胞在脑病理生理学中的研究开辟了新的视角。
