Laboratory of Glial Cell Biology in Health and Disease
RESEARCH
The ultimate goal of the lab´s research is to elucidate the bidirectional communication between neurons and glia in the healthy and diseased brain. How do neurons talk to glia? How does glial function affect neurons? To answer these broad questions, we use a multidisciplinary approach combining in vivo experiments in rodents, and human and monkey brain tissue and plasma samples; and in vitro experiments in primary and organotypic cultures, human induced pluripotent stem cells (iPSCs), human brain organoids, and xenotransplant models. We use a combination of imaging and molecular biology techniques (epigenetic, transcriptomic, proteomic and metabolomic analysis) to dissect out the role of glial cells during development and in diseases such as epilepsy, stroke, Alzheimer’s disease, Multiple Sclerosis and traumatic brain injury.
One research line in our lab is to study microglia as the brain professional phagocytes (PI Sierra). Phagocytosis is not merely an endpoint process to dispose of cell debris but, rather, an active component of the endogenous regenerative response to maintain brain tissue homeostasis during health and disease. We have shown that microglial phagocytosis is very efficient in physiological conditions and it shapes adult hippocampal neurogenesis through the phagocytosis secretome (Sierra et al., Cell Stem Cell 2010; Diaz-Aparicio et al., J Neurosci 2020), and we are currently exploring whether this mechanism is involved in glioblastoma. In contrast, phagocytosis becomes rapidly and chronically impaired in mouse and human epilepsy and stroke (Abiega et al., PLoS Biol 2016; Sierra-Torre et al., 2020; Beccari et al., Autophagy 2023), raising the idea that harnessing phagocytosis is a novel therapeutic target to accelerate the regeneration of the diseased brain (Marquez-Ropero et al., Front Immunol 2019; Rodriguez-Iglesias et al. Glia 2024). We are currently exploring what mechanisms trigger the developmental maturation of microglia as an efficient phagocyte and whether Alzheimer´s disease risk factors alter the developmental trajectory of microglia.
Another liner of research in our lab focuses on elucidating the involvement of Neddylation in glial biology in health and disease (PI Buendia). Neddylation is a post-translational modification that has emerged as a critical regulatory process controlling ubiquitination, protein transcription and signaling transduction. It has been largely explored in the context of nerve growth, synapse strength, and synaptic plasticity, but its impact on glial cells continues to be unexplored. After demonstrating the involvement of neddylation in glial development in the healthy brain, we are examining its role in severe brain injuries, such as Multiple Sclerosis (MS) and traumatic brain injury (TBI), which share demyelination and neuroinflammation as histopathological hallmarks. Both diseases lead to life-changing and debilitating problems for patients, including cognitive, behavioral, and physical disabilities. Currently, there is a direct need for pre-clinical and clinical research for better diagnostic and prognostic tools, as well as an evident need for new therapeutic strategies for which we aim to demonstrate that Neddylation is a good candidate.
PROGRAMME
TECHNIQUES
Stereotaxic surgery, immunofluorescence, epifluorescent and confocal microscopy and electron microscopy, stereology-based quantification, qPCR, gene arrays, ChiPSeq, RNASeq, fluorescent-activated cell sorting, Western blot, Proteomics, Seahorse metabolic analysis, primary cultures, organotypic cultures, in vitro models of phagocytosis, neuroinflammation, iPSCs, human brain organoids, xenotransplants, in vivo models of diseases in WT and KO mice.
LARGE EQUIPMENT
Stoelting stereotaxic surgery set up with Nanoject microcapillary injector; Leica vibratome; Heracell tissue culture incubator; Perimed Doppler cerebral blood flow analyzer.
PUBLICATIONS
People
Principal Investigators
Predoctoral Researchers
Laboratory Technician
Latest publications
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Microglial lipid phosphatase SHIP1 limits complement-mediated synaptic pruning in the healthy developing hippocampus
Immunity (Jan, 2025) DOI: 10.1016/j.immuni.2024.11.003 -
Microglia as hunters or gatherers of brain synapses
Nature Neuroscience (Dec, 2024) DOI: 10.1038/s41593-024-01818-w -
Microglial lipid phosphatase SHIP1 limits complement-mediated synaptic pruning in the healthy developing hippocampus
Immunity (Dec, 2024) DOI: 10.1016/j.immuni.2024.11.003 -
A bottom-up approach identifies the antipsychotic and antineoplastic trifluoperazine and the ribose derivative deoxytubercidin as novel microglial phagocytosis inhibitors
GLIA (Oct, 2024) DOI: 10.1002/glia.24637 -
Microglia in Health and Diseases: Integrative Hubs of the Central Nervous System (CNS)
Cold Spring Harbor Perspectives in Biology (Aug, 2024) DOI: 10.1101/cshperspect.a041366 -
Interferons: Invited guests at the brain’s gala banquet
Neuron (Apr, 2024) DOI: 10.1016/j.neuron.2024.03.010 -
Microglia and meningeal macrophages depletion delays the onset of experimental autoimmune encephalomyelitis
Cell Death & Disease (Jan, 2023) DOI: 10.1038/s41419-023-05551-3 -
Microglial phagocytosis dysfunction in stroke is driven by energy depletion and induction of autophagy
Autophagy (Jan, 2023) DOI: 10.1080/15548627.2023.2165313 -
Microglia states and nomenclature: A field at its crossroads
Neuron (Nov, 2022) DOI: 10.1016/j.neuron.2022.10.020 -
Susceptibility of Female Mice to the Dietary Omega-3/Omega-6 Fatty-Acid Ratio: Effects on Adult Hippocampal Neurogenesis and Glia
International Journal of Molecular Sciences (Mar, 2022) DOI: 10.3390/ijms23063399