3045 – MAPPING MYELOID DIFFERENTIATION IDENTIFIES A CSF1+ VASCULAR NICHE FOR MYELOPOIESIS

Mounting evidence indicates that lineage decisions are controlled by local structures that support differentiation in distinct regions of the bone marrow. Our ability to manipulate hematopoiesis to treat disease has been hampered by our lack of understanding of these anatomical cues. Here we described the development of pipelines to simultaneously image myeloid progenitors together with their offspring, HSC, and endosteal and vascular niches. We found that myeloid progenitors move away from HSC during differentiation. Myeloid progenitors do not localize with each other, instead they localize to different sinusoids where they give rise to clusters of immature cells. Granulocyte, monocyte, and dendritic cell production takes place in different sinusoids suggesting the existence of specialized microenvironments that organize myelopoieis. Indeed, MDP selectively cluster with Ly6Clo monocytes and conventional dendritic cells; and localize to a unique subset of CSF1-expressing sinusoids (8% of all sinusoids), Csf1 deletion in the vasculature disrupted the MDP clusters and their interaction with sinusoids, leading to reduced MDP numbers and differentiation ability, with subsequent loss of Ly6Clo monocytes and dendritic cells. These indicate that there is a specific spatial organization of definitive hematopoiesis and that local cues produced by distinct vascular niches are responsible for this organization.