ROBO4-Mediated Vascular Integrity Regulates the Directionality of Hematopoietic Stem Cell Trafficking

•Endothelial ROBO4 promotes unidirectional HSC trafficking across vessel walls•Sinusoidal endothelial cells mediate HSC extravasation from blood to bone marrow•Vascular integrity prevents HSC escape from bone marrow to blood•Induced vascular permeability rapidly mobilizes HSCs to the blood stream

SummaryDespite the use of hematopoietic stem cells (HSCs) in clinical therapy for over half a century, the mechanisms that regulate HSC trafficking, engraftment, and life-long persistence after transplantation are unclear. Here, we show that the vascular endothelium regulates HSC trafficking into and out of bone marrow (BM) niches. Surprisingly, we found that instead of acting as barriers to cellular entry, vascular endothelial cells, via the guidance molecule ROBO4, actively promote HSC translocation across vessel walls into the BM space. In contrast, we found that the vasculature inhibits the reverse process, as induced vascular permeability led to a rapid increase in HSCs in the blood stream. Thus, the vascular endothelium reinforces HSC localization to BM niches both by promoting HSC extravasation from blood-to-BM and by forming vascular barriers that prevent BM-to-blood escape. Our results uncouple the mechanisms that regulate the directionality of HSC trafficking and show that the vasculature can be targeted to improve hematopoietic transplantation therapies.

Graphical AbstractFigure optionsDownload full-size imageDownload as PowerPoint slide