In situ mapping identifies distinct vascular niches for myelopoiesis

Abstract

Summary In contrast to virtually all other tissues, the anatomy of differentiation in the bone marrow (BM) remains unknown. This is due to a lack of strategies to examine blood cell production in situ, which are required to understand differentiation, lineage commitment decisions, and define how spatial organizing cues inform tissue function. Here we developed approaches to image myelopoiesis and generated atlases of granulocyte and monocyte/dendritic cell differentiation. Granulopoiesis and dendritic/monopoiesis localize to different sinusoids and display lineage-specific spatial and clonal architectures. Acute systemic L. monocytogenes infection induces lineage-specific progenitor clusters through increased progenitor self-renewal, but the different lineages remain spatially separated. Monocyte dendritic cell progenitors (MDP) map with Ly6C lo monocytes and conventional dendritic cells; these localize to a subset of vessels expressing a major regulator of myelopoiesis 1 colony-stimulating-factor 1 (CSF1/ M-CSF). Specific deletion of Csf1 in endothelium disrupted the architecture around MDP and their localization to sinusoids. Subsequently, there were reduced MDP numbers and differentiation ability, and loss of Ly6C lo monocytes and dendritic cells during homeostasis and infection. These data indicate that local cues produced by distinct blood vessels are responsible for specific spatial organization of definitive hematopoiesis.

Differences in Steady-State Erythropoiesis in Different Mouse Bones and Postnatal Spleen

“…The CSF1 sinusoids which support myelopoiesis described by Zhang et al (2021) are a subset of type L vessels in the diaphysis. The higher number of CFU-GM colonies seen in the diaphysis might be due to the higher number of sinusoids in the diaphysis than in the epi- and metaphysis ( Zhang et al, 2021 ). The CSF1 sinusoids might affect the formation of the EBIs, as well as their migration toward the sinusoids as the erythroid differentiation progresses from proerythroblast to orthochromatic erythroblasts on the EBIs ( Yokoyama et al, 2003 ).…”

“…Diaphysis has type L vessels which express lower levels of CD31 and endomucin described as CD31 lo EMCN lo (Kusumbe et al, 2014;Ramasamy et al, 2014Ramasamy et al, , 2016. The CSF1 sinusoids which support myelopoiesis described by Zhang et al (2021) are a subset of type L vessels in the diaphysis. The higher number of CFU-GM colonies seen in the diaphysis might be due to the higher number of sinusoids in the diaphysis than in the epi-and metaphysis (Zhang et al, 2021).…”

“…This might be due to increased/decreased number or intrinsic differences among the central macrophages in the BM microenvironment in the different bones. Zhang et al (2021) recently reported that a small subset of endothelial cells of BM sinusoids expresses the colony-stimulating factor 1 (CSF1). This endothelial cell derived CSF1 regulates the differentiation of myeloid cells ( Zhang et al, 2021 ) suggesting that local cues by different blood vessels might control myeloid differentiation.…”

“… Zhang et al (2021) recently reported that a small subset of endothelial cells of BM sinusoids expresses the colony-stimulating factor 1 (CSF1). This endothelial cell derived CSF1 regulates the differentiation of myeloid cells ( Zhang et al, 2021 ) suggesting that local cues by different blood vessels might control myeloid differentiation. The differences we found in erythropoiesis among the different bones could also be due to these CSF1 producing subtype of sinusoid vessels affecting the differentiation of central macrophages of the EBIs.…”

Connecting the Dots: Resolving the Bone Marrow Niche Heterogeneity

“…Elegant work by Zhang et al revealed that following acute systemic infection, monocyte-dendritic cell progenitors localize to a subset of blood vessels expressing colony-stimulating factor 1 (Csf1), known to be a key regulator of myelopoiesis. Indeed, EC-specific deletion of Csf1, results in a loss of non-classical monocytes and dendritic cells during steady-state and following infection (Zhang et al, 2021). It remains to be elucidated if specialized ECs also support progenitors of lymphoid and erythroid lineages.…”