IPSC-derived microglia export cholesterol to neuronal cells in human brain organoids and promote their maturation
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1006433 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR25679358_1.fastq.gz | Fastqsanger.gz | |||
| SRR25679358_2.fastq.gz | Fastqsanger.gz | |||
| SRR25679359_1.fastq.gz | Fastqsanger.gz | |||
| SRR25679359_2.fastq.gz | Fastqsanger.gz | |||
| SRR25679360_1.fastq.gz | Fastqsanger.gz |
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Project description:iPSC-derived microglia export cholesterol to neuronal cells in human brain organoids and promote their maturation
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Project description:iPSC-derived microglia export cholesterol to neuronal cells in human brain organoids and promote their maturation
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Project description:Microglia are specialised brain-resident macrophages that arise from primitive macrophages colonising the embryonic brain. Microglia contribute to multiple aspects of brain development, but their precise roles in early human brain remain poorly understood due to limited access to relevant tissues. The generation of brain organoids from induced human pluripotent stem cells (iPSC) recapitulates some key features of human embryonic brain development, but current approaches do not incorporate microglia and thus are lacking. Here, we generated microgliasufficient brain organoids by co-culturing brain organoids with primitive-like macrophages generated from the same human iPSC (iMac). In organoid co-cultures, iMac differentiated into cells with microglia-like phenotypes and functions (iMicro), and modulated neuronal progenitor cell (NPC) differentiation, limiting NPC proliferation and promoting axonogenesis. Mechanistically, iMicro contained high levels of PLIN2+ lipid droplets that exported cholesterol and its esters which weretaken up by NPC in the organoids. We also detected PLIN2+ lipid droplet-loaded microglia in mouse and human embryonic brain. Overall, our approach significantly advances current human brain organoid approaches by incorporating microglial
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Project description:Cholesterol import in mammalian cells is mediated by the LDL receptor pathway. Here, we perform a genome-wide CRISPR screen using an endogenous cholesterol reporter and identify >100 genes involved in LDL-cholesterol import. We characterise C18orf8 as a core subunit of the mammalian Mon1-Ccz1 guanidine exchange factor (GEF) for Rab7, required for complex stability and function. C18orf8-deficient cells lack Rab7 activation and show severe defects in late endosome morphology and endosomal LDL trafficking, resulting in cellular cholesterol deficiency. Unexpectedly, free cholesterol accumulates within swollen lysosomes, suggesting a critical defect in lysosomal cholesterol export. We find that active Rab7 interacts with the NPC1 cholesterol transporter and licenses lysosomal cholesterol export. This process is abolished in C18orf8-, Ccz1- and Mon1A/B-deficient cells and restored by a constitutively active Rab7. The trimeric Mon1-Ccz1-C18orf8 (MCC) GEF therefore plays a central role in cellular cholesterol homeostasis coordinating Rab7 activation, endosomal LDL trafficking and NPC1-dependent lysosomal cholesterol export.
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