Abstract
A population of monocytes, known as Ly6Clo monocytes, patrol blood vessels by crawling along the vascular endothelium. Here we show that endothelial cells control their origin through Notch signalling. Using combinations of conditional genetic deletion strategies and cell-fate tracking experiments we show that Notch2 regulates conversion of Ly6Chi monocytes into Ly6Clo monocytes in vivo and in vitro, thereby regulating monocyte cell fate under steady-state conditions. This process is controlled by Notch ligand delta-like 1 (Dll1) expressed by a population of endothelial cells that constitute distinct vascular niches in the bone marrow and spleen in vivo, while culture on recombinant DLL1 induces monocyte conversion in vitro. Thus, blood vessels regulate monocyte conversion, a form of committed myeloid cell fate regulation.
Highlights
The cellular and molecular context of Ly6Clo monocyte development is far from clear
To discriminate monocyte subsets and monocyte progenitor populations in mice we concurrently characterized macrophage and dendritic cell progenitor (MDP), common monocyte progenitor (cMoP), Ly6Chi and Ly6Clo monocytes in bone marrow (BM), spleen and peripheral blood (PB) with common and discriminating markers of monocyte types based on known expression profiles[1,2,3,27]
Recent findings have suggested that Ly6Clo monocytes develop from Ly6Chi monocytes
Summary
The cellular and molecular context of Ly6Clo monocyte development is far from clear. Mice deficient for the transcription factor Nur[77] (Nr4a1), an orphan nuclear receptor, show reduced frequency and survival of Ly6Clo monocytes[13]. Vascular EC are a specialized component of the niche that maintain and regulate stem cells and their immune cell progeny by providing instructive paracrine cues, known as angiocrine factors, in part through expression of Notch ligands[19]. Development of MZ B cells and Esam þ dendritic cell in the splenic niche is dependent on Notch ligand delta-like 1 (Dll1)-Notch[2] signalling[23,24,25]. Because of the intricate relationship of Ly6Clo monocytes with EC we reasoned that blood vessels might be involved in monocyte conversion through a Notch-dependent mechanism. We here show that Notch[2] signalling regulates conversion of Ly6Chi monocytes into Ly6Clo monocytes, which is controlled by Notch ligand Dll[1] expressed by a population of EC present in haematopoietic niches of the BM and spleen. Blood vessels regulate monocyte conversion, a form of committed myeloid cell fate regulation
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