title: CXCR2 and CXCL4 regulate survival and self-renewal of hematopoietic stem/progenitor cells.
abstract: The regulation of hematopoietic stem cell (HSC) survival and self-renewal within the bone marrow (BM) niche is not well understood. We therefore investigated global transcriptomic profiling of normal human HSC/hematopoietic progenitor cells [HPCs], revealing that several chemokine ligands (CXCL1-4, CXCL6, CXCL10, CXCL11, and CXCL13) were upregulated in human quiescent CD34(+)Hoescht(-)Pyronin Y(-) and primitive CD34(+)38(-), as compared with proliferating CD34(+)Hoechst(+)Pyronin Y(+) and CD34(+)38(+) stem/progenitor cells. This suggested that chemokines might play an important role in the homeostasis of HSCs. In human CD34(+) hematopoietic cells, knockdown of CXCL4 or pharmacologic inhibition of the chemokine receptor CXCR2, significantly decreased cell viability and colony forming cell (CFC) potential. Studies on Cxcr2(-/-) mice demonstrated enhanced BM and spleen cellularity, with significantly increased numbers of HSCs, hematopoietic progenitor cell-1 (HPC-1), HPC-2, and Lin(-)Sca-1(+)c-Kit(+) subpopulations. Cxcr2(-/-) stem/progenitor cells showed reduced self-renewal capacity as measured in serial transplantation assays. Parallel studies on Cxcl4 demonstrated reduced numbers of CFC in primary and secondary assays following knockdown in murine c-Kit(+) cells, and Cxcl4(-/-) mice showed a decrease in HSC and reduced self-renewal capacity after secondary transplantation. These data demonstrate that the CXCR2 network and CXCL4 play a role in the maintenance of normal HSC/HPC cell fates, including survival and self-renewal.
authors.affiliation: Paul O'Gorman Leukaemia Research Centre, College of Medical, Veterinary and Life Sciences, Institute of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom;
authors.forename: Amy
authors.initials: A
authors.lastname: Sinclair
authors.affiliation: Paul O'Gorman Leukaemia Research Centre, College of Medical, Veterinary and Life Sciences, Institute of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom;
authors.forename: Laura
authors.initials: L
authors.lastname: Park
authors.affiliation: Paul O'Gorman Leukaemia Research Centre, College of Medical, Veterinary and Life Sciences, Institute of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom;
authors.forename: Mansi
authors.initials: M
authors.lastname: Shah
authors.affiliation: Paul O'Gorman Leukaemia Research Centre, College of Medical, Veterinary and Life Sciences, Institute of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom;
authors.forename: Mark
authors.initials: M
authors.lastname: Drotar
authors.affiliation: Centre for Cardiovascular and Metabolic Research, University of Hull, Hull, United Kingdom;
authors.forename: Simon
authors.initials: S
authors.lastname: Calaminus
authors.affiliation: Paul O'Gorman Leukaemia Research Centre, College of Medical, Veterinary and Life Sciences, Institute of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom;
authors.forename: Lisa E M
authors.initials: LE
authors.lastname: Hopcroft
authors.affiliation: Paul O'Gorman Leukaemia Research Centre, College of Medical, Veterinary and Life Sciences, Institute of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom;
authors.forename: Ross
authors.initials: R
authors.lastname: Kinstrie
authors.affiliation: Medical Research Council Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, United Kingdom;
authors.forename: Amelie V
authors.initials: AV
authors.lastname: Guitart
authors.affiliation: Paul O'Gorman Leukaemia Research Centre, College of Medical, Veterinary and Life Sciences, Institute of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom;
authors.forename: Karen
authors.initials: K
authors.lastname: Dunn
authors.affiliation: Paul O'Gorman Leukaemia Research Centre, College of Medical, Veterinary and Life Sciences, Institute of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom;
authors.forename: Sheela A
authors.initials: SA
authors.lastname: Abraham
authors.affiliation: Beatson Institute for Cancer Research, Glasgow, United Kingdom; and.
authors.forename: Owen
authors.initials: O
authors.lastname: Sansom
authors.affiliation: Paul O'Gorman Leukaemia Research Centre, College of Medical, Veterinary and Life Sciences, Institute of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom;
authors.forename: Alison M
authors.initials: AM
authors.lastname: Michie
authors.affiliation: Beatson Institute for Cancer Research, Glasgow, United Kingdom; and.
authors.forename: Laura
authors.initials: L
authors.lastname: Machesky
authors.affiliation: Medical Research Council Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, United Kingdom;
authors.forename: Kamil R
authors.initials: KR
authors.lastname: Kranc
authors.affiliation: Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom.
authors.forename: Gerard J
authors.initials: GJ
authors.lastname: Graham
authors.affiliation: Paul O'Gorman Leukaemia Research Centre, College of Medical, Veterinary and Life Sciences, Institute of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom;
authors.forename: Francesca
authors.initials: F
authors.lastname: Pellicano
authors.affiliation: Paul O'Gorman Leukaemia Research Centre, College of Medical, Veterinary and Life Sciences, Institute of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom;
authors.forename: Tessa L
authors.initials: TL
authors.lastname: Holyoake
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000378:metabolism; D049109:Cell Proliferation / Q000502:physiology*; D002470:Cell Survival / Q000502:physiology; D005260:Female; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010978:Platelet Factor 4 / Q000378:metabolism*; D023063:Receptors, Interleukin-8B / Q000235:genetics / Q000378:metabolism*; D013154:Spleen / Q000166:cytology / Q000378:metabolism
chemical_list: D023063:Receptors, Interleukin-8B; D010978:Platelet Factor 4