OZR Back-up mandate: Uncovering the dynamics of adult microglial engraftment as foundation for brain macrophage replacement therapy

Microglia are key regulators of healthy brain physiology and play an important role in inflammation and disease. Microglial dysfunction has been convincingly linked to a myriad of neurological disorders, making these cells an important target for therapeutic intervention. Microglia are embryonically-derived cells that self-maintain throughout life and exhibit a striking self-renewal capacity. Therefore, these cells form an attractive target for cell therapy, with the rationale of replacing embryonic microglia with gene-engineered counterparts that ameliorate disease. In this project, we aim to lay the foundations for future microglial transplantation therapies. We will rely on cuttingedge technologies and innovative mouse models, to reveal the ability of discrete bone marrow progenitors or iPSC-derived precursors to engraft the brain as microglia-like cells. By using single-cell RNA sequencing and in vivo 2-photon microscopy, we will delineate the cellular and transcriptional dynamics of progenitor-to-microglia differentiation. Furthermore, we will assess the ability of the engrafted microglial populations to self-renew and to compete with embryonic microglia. Finally, we aim to develop an efficient strategy for bone marrow- or iPSC-based microglial replacement that can be translated to human patients. This work holds the potential of introducing a new treatment paradigm for brain disease.