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

摘要

Despite 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 regulatesHSC 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 inthe blood stream. Thus, the vascular endothelium reinforces HSC localization to BM niches both by promoting HSC extravasation fromblood-to-BM and by forming vascular barriers that prevent BM-to-blood escape. Our results uncouple the mechanisms that regulate thedirectionality of HSC trafficking and show that the vasculature can be targeted to improve hematopoietic transplantation therapies.