Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Gene regulatory networks underlying human microglia maturation [ATAC-seq]

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE226690 | GEO | 2023/08/14

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Gene regulatory networks underlying human microglia maturation [RNA-seq]

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

Development of a chimeric model to study and manipulate human microglia in vivo (scRNA-seq dataset)

Project description:iPSC-derived microglia offer a powerful tool to study microglial homeostasis and disease-associated inflammatory responses. Yet, microglia are highly sensitive to their environment, exhibiting transcriptomic deficiencies when kept in isolation from the brain. Furthermore, species-specific genetic variations demonstrate that rodent microglia fail to fully recapitulate the human condition. To address this, we developed an approach to study human microglia within a surrogate brain environment. Transplantation of iPSC-derived hematopoietic-progenitors into the postnatal brain of humanized, immune-deficient mice results in context-dependent differentiation into microglia and other CNS macrophages, acquisition of an ex vivo human microglial gene signature, and responsiveness to both acute and chronic insults. Most notably, transplanted microglia exhibit robust transcriptional responses to Ab-plaques that only partially overlap with that of murine microglia, revealing new, human-specific Ab-responsive genes. We therefore have demonstrated that this chimeric model provides a powerful new system to examine the in vivo function of patient-derived and genetically-modified microglia.

2019-07-30 | GSE133433 | GEO

Development of a chimeric model to study and manipulate human microglia in vivo (bulk RNA-seq dataset)

2019-07-30 | GSE133432 | GEO

Microglial SHIP1 controls synaptic pruning in the developing hippocampus via the complement system

Project description:INPP5D, which encodes the lipid phosphatase SHIP1, is one of the most common genes associated with the risk of Alzheimer’s disease and is enriched in microglia in the central nervous system. SHIP1 has been found to be highly expressed in plaque-associated microglia. However, how it regulates microglial function and influences brain physiology has been poorly investigated. Here we show that SHIP1 is not only enriched in microglia associated with amyloid beta plaques, but also in early stages of healthy brain development. By combining in vivo loss-of-function approaches and proteomics, we discovered that conditional knockout mice lacking microglial SHIP1 (cKO) display increased complement and synapse loss in the early postnatal brain. Additionally, SHIP1 KO microglia show reduced morphological complexity, altered transcriptional signatures, and abnormal synaptic pruning, which is dependent on the complement system. Single nucleus RNA-sequencing analysis of the entire hippocampus confirmed decreased interaction for synaptic structure-related pathways in both excitatory and inhibitory neurons. Importantly, cKO mice show cognitive defects in adulthood only when microglial SHIP1 is depleted at early postnatal days, but not when depleted at later stages. Finally, using CRISPR/Cas9 we generated human iPSC-derived microglia lacking SHIP1, and validated the increased engulfment of synaptic structures. Altogether, these findings suggest that SHIP1 is essential for proper microglia-mediated synapse remodeling through the complement system in the early postnatal brain. Disrupting this process has lasting behavioral effects and may provide a link to vulnerability to neurodegeneration.

2024-12-04 | PXD052118 | Pride

Therapeutic potential of human microglial transplantation in a chimeric model of CSF1R-related leukoencephalopathy

Project description:Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) is a rare, autosomal dominant primary microgliopathy caused by mutations in colony-stimulating factor 1 receptor (CSF1R). CSF1R signaling is necessary for microglial differentiation and survival. As a result, ALSP patient brains have fewer microglia and exhibit an array of neuropathologies including axonal spheroids, white matter abnormalities, reactive astrocytosis, and brain calcification. To explore the therapeutic potential of transplanting healthy human microglia, we generated ‘hFIRE’ mice, a xenotolerant mouse model of ALSP that lacks murine microglia. Remarkably, transplantation of induced pluripotent stem cell (iPSC)-derived microglial progenitors enabled rapid CNS-wide microglial engraftment, restoring a homeostatic microglial gene signature and preventing diverse ALSP-related neuropathologies. To further examine a potential autologous approach, ALSP-patient derived iPSCs were CRISPR-corrected, rescuing mutation-induced deficits in microglial proliferation, enabling brain-wide microglial engraftment, and reducing pre-existing spheroid, astroglial, and calcification pathologies within just 6 weeks. Together with the accompanying study by Munro and Colleagues, these results demonstrate the utility of FIRE mice to model diverse ALSP neuropathologies and provide initial evidence that iPSC-microglia could be further developed as a promising new therapeutic strategy for ALSP and perhaps other microglia-associated neurological disorders.

2024-04-24 | GSE253623 | GEO

Microglia and brain organoids

Project description:iPSC-derived microglia export cholesterol to neuronal cells in human brain organoids and promote their maturation

2023-05-19 | PXD042344 | JPOST Repository

iPSC-derived microglia export cholesterol to neuronal cells in human brain organoids and promote their maturation

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

iPSC-derived microglia export cholesterol to neuronal cells in human brain organoids and promote their maturation

2023-11-15 | GSE241127 | GEO

Induced pluripotent stem cell-derived primitive macrophages as a cellular platform to model tissue-resident macrophage differentiation and function

Project description:Specialized tissue macrophages arise during embryogenesis from yolk-sac (YS) progenitors that migrate into developing tissues and terminally differentiate in situ. Until recently, it has been impossible to isolate or derive sufficient numbers of YS-derived macrophages for further study, but data now suggest that induced pluripotent stem cells (iPSCs) can be driven to undergo a process reminiscent of YS-hematopoiesis in vitro. We asked whether iPSC-derived primitive macrophages (iMac) can terminally differentiate into specialized macrophages using growth factors and organ-specific cues. Co-culturing murine iMac with iPSC-derived neurons promoted differentiation into microglia-like cells in vitro. Furthermore, murine iMac differentiated in vivo into microglia following injection into the brain, and functional alveolar macrophages after engraftment in the lung.

2017-07-20 | GSE99078 | GEO

Peripherally derived macrophages can engraft the brain independent of irradiation and maintain an identity distinct from microglia [GFP]

Project description:Peripherally derived macrophages infiltrate the brain after bone marrow transplantation and during central nervous system (CNS) inflammation. It was initially suggested that these engrafting cells were newly derived microglia and that irradiation was essential for engraftment to occur. However, it remains unclear whether brain-engrafting macrophages (beMφs) acquire a unique phenotype in the brain, whether long-term engraftment may occur without irradiation, and whether brain function is affected by the engrafted cells. In this study, we demonstrate that chronic, partial microglia depletion is sufficient for beMφs to populate the niche and that the presence of beMφs does not alter behavior. Furthermore, beMφs maintain a unique functional and transcriptional identity as compared with microglia. Overall, this study establishes beMφs as a unique CNS cell type and demonstrates that therapeutic engraftment of beMφs may be possible with irradiation-free conditioning regimens.

2018-04-07 | GSE108569 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data