Three-dimensional mapping identifies distinct vascular niches for myelopoiesis

Abstract

In contrast to virtually all other tissues in the body the anatomy of differentiation in the bone marrow remains unknown. This is due to the lack of strategies to examine blood cell production in situ, which are required to better understand differentiation, lineage commitment decisions, and to define how spatial organizing cues inform tissue function. Here we developed imaging approaches to map all myeloid cells in whole bones and generated 3D atlases of granulocyte and monocyte/dendritic cell differentiation during homeostasis. We found that myeloid progenitors leave the hematopoietic stem cell niche during differentiation. Granulocyte and monocyte dendritic cell progenitors (MDP) do not interact, instead they localize to different sinusoids where they give rise to clusters of immature cells. MDP cluster with Ly6Clo monocytes and conventional dendritic cells; these localize to a unique subset of colony stimulating factor 1 (CSF1, the major regulator of monopoiesis1) -expressing 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 peripheral Ly6Clo monocytes and dendritic cells. These data indicate that there is a specific spatial organization of definitive hematopoiesis and that local cues produced by distinct blood vessels are responsible for this organization. These maps provide a blueprint for in situ analyses of hematopoiesis in blood disorders.