title: ROBO4-mediated vascular integrity regulates the directionality of hematopoietic stem cell trafficking.
abstract: 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 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.
authors: Institute for the Biology of Stem Cells, Department of Biomolecular Engineering, University of California, Santa Cruz, Santa Cruz, CA 95064, USA.
authors: Stephanie
authors: S
authors: Smith-Berdan
authors: Institute for the Biology of Stem Cells, Department of Biomolecular Engineering, University of California, Santa Cruz, Santa Cruz, CA 95064, USA.
authors: Andrew
authors: A
authors: Nguyen
authors: Institute for the Biology of Stem Cells, Department of Biomolecular Engineering, University of California, Santa Cruz, Santa Cruz, CA 95064, USA.
authors: Matthew A
authors: MA
authors: Hong
authors: Institute for the Biology of Stem Cells, Department of Biomolecular Engineering, University of California, Santa Cruz, Santa Cruz, CA 95064, USA. Electronic address: cforsber@soe.ucsc.edu.
authors: E Camilla
authors: EC
authors: Forsberg
mesh_terms: D000818:Animals; D001808:Blood Vessels / Q000502:physiology*; D001853:Bone Marrow / Q000502:physiology; D002199:Capillary Permeability / Q000187:drug effects / Q000235:genetics; D002465:Cell Movement / Q000235:genetics*; D042783:Endothelial Cells / Q000378:metabolism; D017353:Gene Deletion; D006085:Graft Survival / Q000235:genetics; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D023421:Models, Animal; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism*; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic / Q000235:genetics* / Q000378:metabolism*; D057705:Transendothelial and Transepithelial Migration / Q000187:drug effects / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology
chemical_list: D009419:Nerve Tissue Proteins; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic; C540792:Robo4 protein, mouse; D042461:Vascular Endothelial Growth Factor A
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