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Stem-cell-derived human microglia transplanted into mouse brain to study human disease University of Antwerp

Nicola Fattorelli, Anna Martinez-Muriana, Leen Wolfs, Ivana Geric, Bart De Strooper, Renzo Mancuso
Microglia are critically involved in complex neurological disorders with a strong genetic component, such as Alzheimer's disease, Parkinson's disease and frontotemporal dementia. Although mouse microglia can recapitulate aspects of human microglia physiology, they do not fully capture the human genetic aspects of disease and do not reproduce all human cell states. Primary cultures of human microglia or microglia derived from human induced ...

Stem-cell-derived human microglia transplanted in mouse brain to study human disease KU Leuven

Renzo Mancuso, Johanna Van Den Daele, Nicola Fattorelli, Sriram Balusu, Adrian Liston, Annerieke Sierksma, Tom Theys, Catherine Verfaillie, Mark Fiers, Bart De Strooper, et al.
Although genetics highlights the role of microglia in Alzheimer's disease, one-third of putative Alzheimer's disease risk genes lack adequate mouse orthologs. Here we successfully engraft human microglia derived from embryonic stem cells in the mouse brain. The cells recapitulate transcriptionally human primary microglia ex vivo and show expression of human-specific Alzheimer's disease risk genes. Oligomeric amyloid-β induces a divergent ...

Human fetal microglia acquire homeostatic immune-sensing properties early in development Ghent University

L. Kracht, M. Borggrewe, S. Eskandar, N. Brouwer, Susana Marina Chuva de Sousa Lopes, J. D. Laman, S. A. Scherjon, J. R. Prins, S. M. Kooistra, B. J. L. Eggen, et al.
Microglia, immune cells of the central nervous system (CNS), are important for tissue development and maintenance and are implicated in CNS disease, but we lack understanding of human fetal microglia development. Single-cell gene expression and bulk chromatin profiles of microglia at 9 to 18 gestational weeks (GWs) of human fetal development were generated. Microglia were heterogeneous at all studied GWs. Microglia start to mature during this ...

Spatial and temporal heterogeneity of mouse and human microglia at single-cell resolution Ghent University

Takahiro Masuda, Roman Sankowski, Ori Staszewski, Chotima Boettcher, Lukas Amann, Christian Scheiwe, Stefan Nessler, Patrik Kunz, Geert van Loo, Volker Arnd Coenen, et al.
Microglia have critical roles not only in neural development and homeostasis, but also in neurodegenerative and neuroinflammatory diseases of the central nervous system(1-4). These highly diverse and specialized functions may be executed by subsets of microglia that already exist in situ, or by specific subsets of microglia that develop from a homogeneous pool of cells on demand. However, little is known about the presence of spatially and ...

Single-nucleus RNA-Seq is not suitable for detection of microglial activation genes in humans University of Antwerp KU Leuven

Nicola Thrupp, Carlo Sala Frigerio, Leen Wolfs, Nathan G. Skene, Nicola Fattorelli, Suresh Poovathingal, Yannick Fourne, Paul M. Matthews, Tom Theys, Renzo Mancuso, et al.
Single-nucleus RNA sequencing (snRNA-seq) is used as an alternative to single-cell RNA-seq, as it allows transcriptomic profiling of frozen tissue. However, it is unclear whether snRNA-seq is able to detect cellular state in human tissue. Indeed, snRNA-seq analyses of human brain samples have failed to detect a consistent microglial activation signature in Alzheimer's disease. Our comparison of microglia from single cells and single nuclei of ...

Microglia lacking a peroxisomal β-oxidation enzyme chronically alter their inflammatory profile without evoking neuronal and behavioral deficits Vrije Universiteit Brussel KU Leuven

Ivana Geric, Sander Beel, Philip Van Damme, Rudi D'Hooge

BACKGROUND: Microglia play a central role in most neurological disorders, but the impact of microgliosis on brain environment and clinical functions is not fully understood. Mice lacking multifunctional protein-2 (MFP2), a pivotal enzyme in peroxisomal β-oxidation, develop a fatal disorder characterized by motor problems similar to the milder form of MFP2 deficiency in humans. The hallmark of disease in mice is the chronic proliferation of ...

The endoplasmic reticulum Ca2+-ATPase SERCA2b is upregulated in activated microglia and its inhibition causes opposite effects on migration and phagocytosis KU Leuven

Peter Vangheluwe
Activation of microglia is an early immune response to damage in the brain. Although a key role for Ca2+ as trigger of microglial activation has been considered, little is known about the molecular scenario for regulating Ca2+ homeostasis in these cells. Taking into account the importance of the endoplasmic reticulum as a cellular Ca2+ store, the sarco(endo)plasmic reticulum Ca2+ -ATPase (SERCA2b) is an interesting target to modulate ...

Increased pyroptosis activation in white matter microglia is associated with neuronal loss in ALS motor cortex KU Leuven

Evelien Van Schoor, Sandra Oliveira Tomé, Philip Van Damme, Ludo Van Den Bosch, Dietmar Thal
Amyotrophic lateral sclerosis (ALS) is characterized by the degeneration of motor neurons in the motor cortex, brainstem, and spinal cord. Although ALS is considered a motor neuron disorder, neuroinflammation also plays an important role. Recent evidence in ALS disease models indicates activation of the inflammasome and subsequent initiation of pyroptosis, an inflammatory type of cell death. In this study, we determined the expression and ...

Neuronal Dysfunction and Behavioral Abnormalities Are Evoked by Neural Cells and Aggravated by Inflammatory Microglia in Peroxisomal β-Oxidation Deficiency Vrije Universiteit Brussel KU Leuven

Rudi D'Hooge

It is becoming evident that microglia, the resident immune cells of the central nervous system (CNS), are active contributors in neurological disorders. Nevertheless, the impact of microgliosis on neuropathology, behavior and clinical decline in neuropathological conditions remains elusive. A mouse model lacking multifunctional protein-2 (MFP2), a pivotal enzyme in peroxisomal β-oxidation, develops a fatal disorder characterized by motor ...