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Adamantinomatous craniopharyngioma cyst fluid can trigger inflammatory activation of microglia to damage the hypothalamic neurons by inducing the production of β-amyloid

ABSTRACT: Introduction: The mechanism by which adamantinomatous craniopharyngioma (ACP) damages the hypothalamus is still unclear. Cyst fuid rich in lipids and infammatory factors is a characteristic pathological manifestation of ACP and may play a very important role in hypothalamic injury caused by tumors. Objective: The objective of this study was to construct a reliable animal model of ACP cyst fuid-induced hypotha lamic injury and explore the specifc mechanism of hypothalamic injury caused by cyst fuid. Methods: An animal model was established by injecting human ACP cyst fuid into the bilateral hypothalamus of mice. ScRNA-seq was performed on the mice hypothalamus and on an ACP sample to obtain a complete gene expression profle for analysis. Data verifcation was performed through pathological means. Results: ACP cystic fuid caused growth retardation and an increased obesity index in mice, afected the expres sion of the Npy, Fgfr2, Rnpc3, Sst, and Pcsk1n genes that regulate growth and energy metabolism in hypothalamic neurons, and enhanced the cellular interaction of Agrp–Mc3r. ACP cystic fuid signifcantly caused infammatory activation of hypothalamic microglia. The cellular interaction of CD74–APP is signifcantly strengthened between infammatory activated microglia and hypothalamic neurons. Beta-amyloid, a marker of neurodegenerative diseases, was deposited in the ACP tumor tissues and in the hypothalamus of mice injected with ACP cyst fuid. Conclusion: In this study, a novel animal model of ACP cystic fuid-hypothalamic injury was established. For the frst time, it was found that ACP cystic fuid can trigger infammatory activation of microglia to damage the hypothalamus, which may be related to the upregulation of the CD74–APP interaction and deposition of β-amyloid, implying that there may be a similar mechanism between ACP cystic fuid damage to the hypothalamus and neurodegenerative diseases.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE206861 | GEO | 2022/06/25

REPOSITORIES: GEO

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Project description:Microglia are the resident immune cells of the central nervous system (CNS) and are derived from yolk sac progenitors. In the embryo, microglia invade the CNS starting at embryonic day 9.5 (E9.5) and continue to colonize alongside neural development. Microglia also mature across development, altering their morphology and expression signatures from embryonic to adult stages, suggesting differing roles for microglia in the developing brain than in the adult. While microglia were originally thought to be resting immune cells responsible for cleaning up cellular debris, studies are now showing that microglia are highly dynamic cells involved in proper postnatal development of the brain and adult neuronal plasticity. Although recent reports have demonstrated that microglia in the embryonic brain are responsive to maternal stress, causing changes in neural development that lead to autistic- and schizophrenic-like behaviours later in life, the actual effects of microglia on embryonic developmental programs are just emerging. Our lab studies the hypothalamus, a brain region that controls a variety of physiologies including energy balance, reproduction, and even parenting behaviors, and it is also responsive to maternal stress. Interestingly, my previous work has shown that that the hypothalamus uniquely is comprised of at least two distinct populations of microglia. The first group of microglia are ramified, and appear to be passively surveying the hypothalamic mantle as we would expect. The second cluster of microglia is amoeboid and activated, and are located adjacent to the ventricular zone (VZ) where hypothalamic neural progenitor cells (NPCs) reside. Given that this second group of microglia is in direct contact with NPCs, we hypothesize that microglia located in the VZ of the hypothalamus play an important role during embryonic development to organize the neurons and neuronal connections required for proper hypothalamic function. In order to identify the expression profiles of microglia in the VZ as compared to microglia present in the mantle of the hypothalamus, we used Cx3cr1-Cre; Rosa26tdTomato mice to mark microglia. We then micro-dissected the hypothalamic/thalamic region of the E15.5 brains and used flow cytometry to extract tdTomato+ microglia. We then performed single-cell RNAseq on the microglia to determine the transcriptomic phenotype of these two populations.

Project description:Microglia are the resident phagocytic immune cells of the central nervous system (CNS). In the embryo, microglia invade the CNS during early embryogenesis and continue to colonize alongside neural development. Microglia also mature across development, altering their morphology and expression signatures from embryonic to adult stages, suggesting differing roles for microglia in the developing brain than in the adult. While microglia were originally thought to be resting immune cells responsible for cleaning up cellular debris, studies are now showing that microglia are highly dynamic cells involved in proper postnatal development of the brain and adult neuronal plasticity. Although reports suggest that microglia in the embryonic brain are responsive to maternal stress, causing changes in neural development that lead to autistic- and schizophrenic-like behaviours later in life, the actual effects of microglia on embryonic developmental programs are just emerging. Our lab studies the hypothalamus, a brain region that controls a variety of physiologies including energy balance, reproduction, and even parenting behaviors, and it is also responsive to maternal stress. Interestingly, my previous work has shown that that the hypothalamus is uniquely comprised of at least two distinct populations of microglia. The first group of microglia are ramified, and appear to be passively surveying the hypothalamic mantle. The second cluster of microglia is amoeboid and activated, and are located adjacent to the ventricular zone (VZ) where hypothalamic neural progenitor cells (NPCs) reside. Given that this second group of microglia is in direct contact with NPCs, we hypothesize that microglia located in the VZ of the hypothalamus play an important role during embryonic development to organize the neurons and neuronal connections required for proper hypothalamic function. In order to identify the expression profiles of microglia in the VZ as compared to microglia present in the mantle of the hypothalamus, we extracted microglia from the brains of CD1 embryos and employed single-cell RNAseq. Specifically, we micro-dissected out the hypothalamic/thalamic region of E15.5 brains, created a single-cell suspension that was stained with Cd11b-PE / Cd45-FITC to mark microglia, and then used FACS to extract microglia from our mixed cell suspension. We then performed single-cell RNAseq on the microglia to determine the transcriptomic phenotype of these two populations either in a control condition or following maternal stress, where pregnant dams were exposed to a mild cold stress for 30 min a day over 5 days.

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Adamantinomatous craniopharyngioma cyst fluid can trigger inflammatory activation of microglia to damage the hypothalamic neurons by inducing the production of β-amyloid

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