Biology subjects

Gigase, F.

Publications and source records attributed to Gigase, F..

3 recordsLinked to original sources

bioRxiv2024

A microglia-containing cerebral organoid model to study early life immune challenges

Prenatal infections and activation of the maternal immune system have been proposed to contribute to causing neurodevelopmental disorders (NDDs), chronic conditions often linked to brain abnormalities. Microglia are the resident immune cells of the brain and play a key role in neurodevelopment. Disruption of microglial functions can lead to brain abnormalities and increase the risk of developing NDDs. How the maternal as well as the fetal immune system affect human neurodevelopment and contribute to NDDs remains unclear. An important reason for this knowledge gap is the fact that the impact of exposure to prenatal risk factors has been challenging to study in the human context. Here, we characterized a model of cerebral organoids (CO) with integrated microglia (COiMg). These organoids express typical microglial markers and respond to inflammatory stimuli. The presence of microglia influences cerebral organoid development, including cell density and neural differentiation, and regulates the expression of several ciliated mesenchymal cell markers. Moreover, COiMg and organoids without microglia show similar but also distinct responses to inflammatory stimuli. Additionally, IFN-{gamma} induced significant transcriptional and structural changes in the cerebral organoids, that appear to be regulated by the presence of microglia. Specifically, interferon-gamma (IFN-{gamma}) was found to alter the expression of genes linked to autism. This model provides a valuable tool to study how inflammatory perturbations and microglial presence affect neurodevelopmental processes.

neuroscience↗

bioRxiv2023

The human microglia responsome: a resource to better understand microglia states in health and disease

Microglia, the immune cells of the brain, are increasingly implicated in neurodegenerative disorders through genetic studies. However, how genetic risk factors for these diseases are related to microglial gene expression, microglial function, and ultimately disease, is still largely unknown. Microglia change rapidly in response to alterations in their cellular environment, which is regulated through changes in transcriptional programs, which are as yet poorly understood. Here, we compared the effects of a set of inflammatory and restorative stimuli (lipopolysaccharide, interferon-gamma, resiquimod, tumor necrosis factor-alpha, adenosine triphosphate, dexamethasone, and interleukin-4) on human microglial cells from 67 different donors (N = 398 samples) at the gene and transcript level. We show that microglia from different anatomical brain regions show distinct responses to inflammatory stimuli. We observed a greater overlap between human stimulated microglia and human monocytes than with mouse microglia. We define specific microglial signatures across conditions which are highly relevant for a wide range of biological functions and complex human diseases. Finally, we used our stimulation signatures to interpret associations from Alzheimers disease (AD) genetic studies and microglia by integrating our inflammatory gene expression profiles with common genetic variants to map cis-expression QTLs (eQTLs). Together, we provide the most comprehensive transcriptomic database of the human microglia responsome. HighlightsO_LIRNA-sequencing of 398 human microglial samples exposed to six different triggers. C_LIO_LIMicroglia from different anatomical regions show distinct stimulation responses. C_LIO_LIResponses in human microglia show a greater overlap with human monocytes than murine microglia. C_LIO_LIMapping of response Quantitative Trait Loci identifies interactions between genotype and effect of stimulation on gene expression. C_LIO_LIOur atlas provides a reference map for interpreting microglia signatures in health and disease. C_LI

neuroscience↗

bioRxiv2020

Atlas of genetic effects in human microglia transcriptome across brain regions, aging and disease pathologies

Microglial cells have emerged as potential key players in brain aging and pathology. To capture the heterogeneity of microglia across ages and regions, and to understand how genetic risk for neurological and psychiatric brain disorders is related to microglial function, large transcriptome studies are essential. Here, we describe the transcriptome analysis of 255 primary human microglia samples isolated at autopsy from multiple brain regions of 100 human subjects. We performed systematic analyses to investigate various aspects of microglial heterogeneities, including brain region, age and sex. We mapped expression and splicing quantitative trait loci and showed that many neurological disease susceptibility loci are mediated through gene expression or splicing in microglia. Fine-mapping of these loci nominated candidate causal variants that are within microglia-specific enhancers, including novel associations with microglia expression of USP6NL for Alzheimers disease, and P2RY12 for Parkinsons disease. In summary, we have built the most comprehensive catalog to date of genetic effects on the microglia transcriptome and propose molecular mechanisms of action of candidate functional variants in several neurological and psychiatric diseases.

genetics↗