Developmental Crosstalk between Microglia and Blood-Brain Barrier – MicroBBB

|The project relies on a combination of imaging, molecular, and genetic approaches in mouse models. Using advanced microscopes, we can observe these cells directly in the developing brain and see how they move, interact, and organize around blood vessels. By analyzing which genes are active in each cell type and how this changes during development, we can identify the molecular messages involved in microglia and BBB communication. We also examine how well the blood-brain barrier is formed and how it functions, using a combination of tissue analysis and imaging techniques. Finally, specific experimental models make it possible to modify microglia or pericytes to see how one cell population influences the other. Together, these different methods provide a detailed picture of how the brain immune and vascular systems develop hand in hand to build a protective and stable environment for neurons.

|Although the project is still ongoing, this research highlights the importance of understanding the close communication between microglia and vascular cells during brain development. These two cell types engage in a dynamic dialogue that appears essential for shaping the developing brain. Better understanding this immunovascular interaction is key to build a more integrated framework of how the brain establishes and maintains its immune protection from early life.

|Understanding how vascular cells and microglia communicate opens new perspectives for developmental and medical research. Disruption of this dialogue may contribute to early vascular fragility or neurodevelopmental disorders. Identifying the molecular signals that link these cells could lead to new strategies to act on BBB integrity, prevent early-life vascular injuries, or improve brain protection.

Beyond the brain, this research raises broader questions about how immune and vascular cells interact in other organs to preserve tissue integrity. The developing brain thus provides a model to understand fundamental biological principles of immunovascular interactions that may apply throughout the body.

In the long term, these insights could help to develop novel therapeutic approaches to modulate microglial or pericyte functions to maintain vascular stability and protect the brain from early-life insults or later neurodegenerative processes.

Brain functioning can be influenced by body ecosystem signals conveyed through the vasculature and regulated by the blood-brain barrier (BBB), a selective and modulable barrier that controls which substances and cells enter or exit the brain. Vasculature or BBB defects have been reported in many brain diseases, from neurodevelopment to neurodegeneration but we still lack knowledge on their causal interplay. Understanding how BBB develop and interact with brain cells in health and disease is thus essential for both neurobiologists and clinicians.
Microglia, the brain resident macrophages, colonize very early on during prenatal life the embryonic brain in which there are in close apposition to the vasculature, but to what extent they interact and regulate each other’s development and function is unclear.
To tackle these issues, we will study the developmental crosstalk between microglia and BBB components at a molecular, cellular and functional level in both females and males. In particular, we will characterize (i) the kinetics and underlying mechanisms of BBB component assembly and their interaction with microglia; (ii) how microglia impact on vascular cells maturation, function and BBB closure; and (iii) how pericytes drive microglial states, maturation and homeostasis. We will use multi-disciplinary approaches in newly developed murine model of microglia depletion, including two-photon live imaging, single-cell and spatial transcriptomics and comparison to human embryos. We will ultimately establish an integrated framework of BBB formation and BBB-microglia crosstalk during fetal life. Our findings will provide key insights into both normal and pathological brain wiring and open research avenues for the identification of therapeutic targets.