title: CXCR2 modulates bone marrow vascular repair and haematopoietic recovery post-transplant.
abstract: Murine models of bone marrow transplantation show that pre-conditioning regimens affect the integrity of the bone marrow endothelium and that the repair of this vascular niche is an essential pre-requisite for successful haematopoietic stem and progenitor cell engraftment. Little is known about the angiogenic pathways that play a role in the repair of the human bone marrow vascular niche. We therefore established an in vitro humanized model, composed of bone marrow stromal and endothelial cells and have identified several pro-angiogenic factors, VEGFA, ANGPT1, CXCL8 and CXCL16, produced by the stromal component of this niche. We demonstrate for the first time that addition of CXCL8 or inhibition of its receptor, CXCR2, modulates blood vessel formation in our bone marrow endothelial niche model. Compared to wild type, Cxcr2(-/-) mice displayed a reduction in bone marrow cellularity and delayed platelet and leucocyte recovery following myeloablation and bone marrow transplantation. The delay in bone marrow recovery correlated with impaired bone marrow vascular repair. Taken together, our data demonstrate that CXCR2 regulates bone marrow blood vessel repair/regeneration and haematopoietic recovery, and clinically may be a therapeutic target for improving bone marrow transplantation.
authors.affiliation: Stem Cell Research Laboratory, NHS Blood and Transplant, John Radcliffe Hospital, Oxford, UK; Nuffield Division of Clinical and Laboratory Sciences, Radcliffe Department of Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK.
authors.forename: Sarah J M
authors.initials: SJ
authors.lastname: Hale
authors.forename: Ashley B H
authors.initials: AB
authors.lastname: Hale
authors.forename: Youyi
authors.initials: Y
authors.lastname: Zhang
authors.forename: Dominic
authors.initials: D
authors.lastname: Sweeney
authors.forename: Nita
authors.initials: N
authors.lastname: Fisher
authors.forename: Mark
authors.initials: M
authors.lastname: van der Garde
authors.forename: Rita
authors.initials: R
authors.lastname: Grabowska
authors.forename: Emma
authors.initials: E
authors.lastname: Pepperell
authors.forename: Keith
authors.initials: K
authors.lastname: Channon
authors.forename: Enca
authors.initials: E
authors.lastname: Martin-Rendon
authors.forename: Suzanne M
authors.initials: SM
authors.lastname: Watt
mesh_terms: D042501:Angiogenic Proteins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001853:Bone Marrow / Q000098:blood supply*; D016026:Bone Marrow Transplantation; D002460:Cell Line; D006410:Hematopoiesis; D018380:Hematopoietic Stem Cell Transplantation; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D018919:Neovascularization, Physiologic; D023063:Receptors, Interleukin-8B / Q000235:genetics / Q000378:metabolism*; D019172:Transplantation Conditioning
chemical_list: D042501:Angiogenic Proteins; D023063:Receptors, Interleukin-8B
keywords: CXCL8; CXCR2; bone marrow transplantation; bone marrow vascular niche; stem cell niche