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Droplet-based scRNA-seq of plasma-positive microglia and plasma-negative microglia from hypothalamus region in young mice

ABSTRACT: Microglia are highly responsive to their local environment and signals from the periphery. Blood plasma proteins readily permeate the healthy brain parenchyma. However, whether microglia are responsive to such proteins is unclear. Here, we identify a stable population of microglia takes up plasma proteins in a region-specific manner in healthy brains. To understand these two populations at the single cell transcriptomic level, we sorted plasma-positive microglia and plasma-negative microglia from hypothalamus region of young mice (3-month-old) and perform droplet-based scRNA-seq.

ORGANISM(S): Mus musculus

PROVIDER: GSE264113 | GEO | 2024/10/15

REPOSITORIES: GEO

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Project description:SPEACC-seq is a novel high-throughput method which enables forward genetic screens to identify cell-cell interaction mechanisms that uncovered an astrocyte-microglia regulatory circuit mediated by amphiregulin and IL33-ST2. signaling. Cell-cell interactions in the central nervous system (CNS) play central roles in neurologic diseases. However, little is known about the specific molecular pathways involved, and methods for their systematic identification are limited. For example, several factors mediate microglia-astrocyte interactions that promote CNS pathology, but less is known about regulatory interactions that limit tissue pathology. Here we report the development of SPEACC-seq (Stimulation, Perturbation, and Encapsulation of interACting Cells followed by Sequencing), a forward genetic screening platform which combines genome-wide CRISPR/Cas9 perturbations, cell co-culture in picoliter droplets, and microfluidic-based fluorescence activated droplet sorting to identify mechanisms of cell-cell communication. Using SPEACC-seq in combination with an in vivo perturb-seq screen, we identified microglia-produced amphiregulin as a suppressor of disease promoting astrocyte responses in experimental autoimmune encephalomyelitis (EAE), a pre-clinical model of multiple sclerosis (MS). The production of microglial amphiregulin was induced via ST2 signaling by IL-33 released from astrocytes during EAE. Indeed, the genetic inactivation of ST2 or amphiregulin in microglia, or IL-33 or amphiregulin signaling in astrocytes resulted in the worsening of EAE, suggesting that IL-33-induced microglial amphiregulin limits disease-promoting astrocyte responses associated with CNS pathology. This regulatory loop was also detected in human astrocytes and microglia both in vitro and in MS patient CNS samples. In summary, we developed SPEACC-seq, a high-throughput, droplet-based forward genetic screening platform for the identification of cell-cell interaction mechanisms, which identified a novel microglia-astrocyte negative feedback loop that limits CNS pathology.

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Droplet-based scRNA-seq of plasma-positive microglia and plasma-negative microglia from hypothalamus region in young mice

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