IPSC-derived microglia export cholesterol to neuronal cells in human brain organoids and promote their maturation
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1015241 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR26034061_1.fastq.gz | Fastqsanger.gz | |||
| SRR26034061_2.fastq.gz | Fastqsanger.gz | |||
| SRR26034062_1.fastq.gz | Fastqsanger.gz | |||
| SRR26034062_2.fastq.gz | Fastqsanger.gz | |||
| SRR26034063_1.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 64 |
Similar Datasets
Project description:iPSC-derived microglia export cholesterol to neuronal cells in human brain organoids and promote their maturation
2023-05-19 | PXD042344 | JPOST Repository
Project description:iPSC-derived microglia export cholesterol to neuronal cells in human brain organoids and promote their maturation
| PRJNA1006433 | ENA
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
2023-09-16 | GSE242894 | GEO
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
2023-11-15 | GSE241127 | GEO
Project description:To compare the proteome between PFN1 mutant and PFN1 WT iPSC-microglia under baseline conditions
2024-02-18 | PXD038943 | Pride
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.
2020-10-29 | PXD021444 | Pride
Project description:Microglia, the tissue resident macrophages of the brain, are observed as early as the fourth week of human gestation and engage in a variety of processes essential for brain development and homeostasis. Microglia phenotypes are highly regulated by the brain environment but the transcriptional networks that specify their maturation remain poorly understood and the extent to which fetal or postnatal phenotypes can be modeled using iPSC-derived cells has not been systematically investigated. Here, we characterized stage-specific transcriptomes and epigenetic landscapes of fetal and postnatal human microglia ex vivo and acquired corresponding data in iPSC-derived microglia in vitro, in cerebral organoids, and as a function of time following engraftment into humanized mice. By developing new computational approaches that integrate these data to predict state-specific transcription factor networks, we provide evidence that MiTF/TFE and MEF2 factors are key nodes in transcription factor networks associated with fetal microglia phenotypes, whereas MAFB, KLFs and IRF transcription factors are key nodes in the networks associated with postnatal phenotypes. We further demonstrate that many features of the human fetal to postnatal transition in microglia gene expression are recapitulated in a time-dependent manner following the engraftment of iPSC-derived hematopoietic progenitor cells into humanized mice. These studies thereby provide new computational and data resources enabling the elucidation of transcription factor networks underlying stage-specific human microglia phenotypes.
2023-08-14 | GSE226705 | GEO
Project description:Microglia, the tissue resident macrophages of the brain, are observed as early as the fourth week of human gestation and engage in a variety of processes essential for brain development and homeostasis. Microglia phenotypes are highly regulated by the brain environment but the transcriptional networks that specify their maturation remain poorly understood and the extent to which fetal or postnatal phenotypes can be modeled using iPSC-derived cells has not been systematically investigated. Here, we characterized stage-specific transcriptomes and epigenetic landscapes of fetal and postnatal human microglia ex vivo and acquired corresponding data in iPSC-derived microglia in vitro, in cerebral organoids, and as a function of time following engraftment into humanized mice. By developing new computational approaches that integrate these data to predict state-specific transcription factor networks, we provide evidence that MiTF/TFE and MEF2 factors are key nodes in transcription factor networks associated with fetal microglia phenotypes, whereas MAFB, KLFs and IRF transcription factors are key nodes in the networks associated with postnatal phenotypes. We further demonstrate that many features of the human fetal to postnatal transition in microglia gene expression are recapitulated in a time-dependent manner following the engraftment of iPSC-derived hematopoietic progenitor cells into humanized mice. These studies thereby provide new computational and data resources enabling the elucidation of transcription factor networks underlying stage-specific human microglia phenotypes.
2023-08-14 | GSE226690 | GEO
Project description:Neuroinflammation is a major component in the transition to and perpetuation of neuropathic pain states. Spinal neuroinflammation involves activation of TLR4, localized to enlarged, cholesterol-enriched lipid rafts, designated here as inflammarafts. Conditional deletion of cholesterol transporters ABCA1 and ABCG1 in microglia, leading to inflammaraft formation, induced tactile allodynia in naïve mice. The apoA-I binding protein (AIBP) facilitated cholesterol depletion from inflammarafts and reversed neuropathic pain in a model of chemotherapy-induced peripheral neuropathy (CIPN) in wild-type mice, but AIBP failed to reverse allodynia in mice with ABCA1/ABCG1-deficient microglia, suggesting a cholesterol-dependent mechanism. An AIBP mutant lacking the TLR4-binding domain did not bind microglia nor reversed CIPN allodynia. The long-lasting therapeutic effect of a single AIBP dose in CIPN was associated with anti-inflammatory and cholesterol metabolism reprogramming and reduced accumulation of lipid droplets in microglia. These results suggest a cholesterol-driven mechanism of regulation of neuropathic pain by controlling TLR4 inflammarafts and gene expression program in microglia and blocking the perpetuation of neuroinflammation.
2021-04-16 | GSE154816 | GEO
Project description:Iron accumulation in microglia has been observed in Alzheimer’s disease and other neurodegenerative disorders and is thought to contribute to disease progression through various mechanisms including neuroinflammation. To study the interaction between iron accumulation and inflammation, we treated human induced pluripotent stem cell-derived microglia (iPSC-MG) with an increasing concentration of iron, in combination with inflammatory stimuli such as interferon gamma and amyloid β, and performed RNA sequencing.
| EGAS00001006112 | EGA