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Human cortical organoids with engineered microglia-like cells [scRNA-Seq] Apr 05, 2024 pending None

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE175722 | GEO | 2021/12/21

REPOSITORIES: GEO

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Human cortical organoids with engineered microglia-like cells [scRNA-Seq] Apr 05, 2024 pending None

Project description:Human cortical organoids with engineered microglia-like cells [scRNA-Seq] Apr 05, 2024 pending None

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Human cortical organoids with engineered microglia-like cells [scRNA-Seq]

Project description:Microglia play vital roles in the emergence and preservation of a healthy brain microenvironment with their impaired functions highlighted in neurodevelopmental and neurodegenerative disorders. However, investigating the microglia function in health and disease states has been challenging due to the lack of easily accessible human models. Here, we develop a method to generate functional microglia inside human cortical organoids (hCOs) from human embryonic stem cells (hESCs) and apply this system to dissect the role of microglia under inflammation induced by amyloid- (A). The overexpression of the myeloid-specific transcription factor PU.1 generated microglia-like cells in hCOs, producing mhCOs (microglia-containing hCOs) and engrafted in the mouse brain. Single-cell transcriptomics reveals that mhCOs acquire a microglia cell cluster with an intact complement/chemokine system. Functionally, microglia in mhCOs protect parenchyma from cellular and molecular damage caused by A. A-induced expression of genes associated with apoptosis, ferroptosis, and Alzheimer’s disease (AD) stage III genes was attenuated in mhCOs. Finally, we determined the function of AD-associated genes highly expressed in microglia in response to A by using pooled CRISPRi coupled with single-cell RNA sequencing in mhCOs. Together, mhCOs represent an innovative platform to investigate neurodegenerative disorders and serve to develop therapeutics in the future.

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Human cortical organoids with engineered microglia-like cells [scRNA-Seq]

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Project description:Human cortical organoids with engineered microglia-like cells [CROP-seq]

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Microglia innately develop within cerebral organoids.

Project description:Cerebral organoids are 3D stem cell-derived models that can be utilized to study the human brain. The current consensus is that cerebral organoids consist of cells derived from the neuroectodermal lineage. This limits their value and applicability, as mesodermal-derived microglia are important players in neural development and disease. Remarkably, here we show that microglia can innately develop within a cerebral organoid model and display their characteristic ramified morphology. The transcriptome and response to inflammatory stimulation of these organoid-grown microglia closely mimic the transcriptome and response of adult microglia acutely isolated from post mortem human brain tissue. In addition, organoid-grown microglia mediate phagocytosis and synaptic material is detected inside them. In all, our study characterizes a microglia-containing organoid model that represents a valuable tool for studying the interplay between microglia, macroglia, and neurons in human brain development and disease.

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Project description:This SuperSeries is composed of the SubSeries listed below.

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