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Microglia are the immune cells of the brain parenchyma. They are constantly sensing and responding to the brain environment. Several microglia states have been detected in neurodegenerative diseases, such as Alzheimer’s disease and Amyotrophic Lateral Sclerosis, each with a specific transcriptomic and proteomic signature suggesting essential roles in diseases. Using human stem cell models and single-cell omics, we aim to identify, track and manipulate microglia states to determine how they become awry in disease and their impact on patients’ symptoms.
Microglia in diseases
Histological and transcriptomics changes in specific populations of microglia are pathological hallmarks of neurodegenerative diseases , including late-onset Alzheimer's Disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). However, it is unknown how these subpopulations, or states, of microglia arise, and if they are protective or detrimental in disease contexts.
Our work is grounded in the genetics of neurodegenerative diseases and aims to compare microglial phenotypes across diseases. iPSC-derived microglia allows us to generate “villages”, or pooled cultures, that combine cells with different genetic backgrounds in the same dish, permitting a high throughput design to analyze up to 100 cell lines simultaneously. Using cell villages to identify phenotypes across multiple genetic backgrounds we will identify the consequences of disease variants on microglia states and functions, and bridge the gap between transcriptomic signatures and altered neuroimmune interactions in neurodegeneration.
For more details on our projects.
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Aging
Dysfunctions leading to neurodegeneration usually start late in life, making aging one of the leading risk factors for these diseases. Aging affects multiple cell-autonomous and non-cell-autonomous aspects in and outside the brain, making it challenging to study how microglia functions change systematically. We want to identify how the aging brain environment and known longevity signaling pathways affect microglia states and functions.
Leveraging a combination of xenograft and in vitro models, we will identify what are the characteristics of aged microglia and mechanistically dissect the impact of known longevity pathways so we can pinpoint how aging and genetic susceptibility to neurodegenerative diseases interact to modify neuro-immune interactions.
Tool development
Microglia represent 5-10% of brain cells and are highly dynamic. In vitro models are easy to scale to increase the number of cells and allow for quick environmental or genetic manipulation. Using a human stem cell model which recapitulates microglia states (Dolan*, Therrien et al Nature Immunology 2023), we want to identify markers to track microglia plasticity and determine how to manipulate specific states to understand they impact brain functions
Collaborations
We believe science should be accessible, reproducible and shared as soon as possible. We aim to bring communities together and share our resources as widely as possible. Do not hesitate to reach out if you would like more details on our protocols, cell lines and resources.
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