title: SDF-1 dynamically mediates megakaryocyte niche occupancy and thrombopoiesis at steady state and following radiation injury.
abstract: Megakaryocyte (MK) development in the bone marrow progresses spatially from the endosteal niche, which promotes MK progenitor proliferation, to the sinusoidal vascular niche, the site of terminal maturation and thrombopoiesis. The chemokine stromal cell-derived factor-1 (SDF-1), signaling through CXCR4, is implicated in the maturational chemotaxis of MKs toward sinusoidal vessels. Here, we demonstrate that both IV administration of SDF-1 and stabilization of endogenous SDF-1 acutely increase MK-vasculature association and thrombopoiesis with no change in MK number. In the setting of radiation injury, we find dynamic fluctuations in marrow SDF-1 distribution that spatially and temporally correlate with variations in MK niche occupancy. Stabilization of altered SDF-1 gradients directly affects MK location. Importantly, these SDF-1-mediated changes have functional consequences for platelet production, as the movement of MKs away from the vasculature decreases circulating platelets, while MK association with the vasculature increases circulating platelets. Finally, we demonstrate that manipulation of SDF-1 gradients can improve radiation-induced thrombocytopenia in a manner additive with earlier TPO treatment. Taken together, our data support the concept that SDF-1 regulates the spatial distribution of MKs in the marrow and consequently circulating platelet numbers. This knowledge of the microenvironmental regulation of the MK lineage could lead to improved therapeutic strategies for thrombocytopenia.
authors.affiliation: Center for Pediatric Biomedical Research, Department of Pediatrics, and Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY.
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Niswander
authors.affiliation: Center for Pediatric Biomedical Research, Department of Pediatrics, and.
authors.forename: Katherine H
authors.initials: KH
authors.lastname: Fegan
authors.affiliation: Center for Pediatric Biomedical Research, Department of Pediatrics, and.
authors.forename: Paul D
authors.initials: PD
authors.lastname: Kingsley
authors.affiliation: Center for Pediatric Biomedical Research, Department of Pediatrics, and.
authors.forename: Kathleen E
authors.initials: KE
authors.lastname: McGrath
authors.affiliation: Center for Pediatric Biomedical Research, Department of Pediatrics, and.
authors.forename: James
authors.identifier: http://orcid.org/0000-0001-7324-1049
authors.initials: J
authors.lastname: Palis
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D002478:Cells, Cultured; D054377:Chemokine CXCL12 / Q000008:administration & dosage / Q000502:physiology*; D005260:Female; D055016:Megakaryocyte Progenitor Cells / Q000166:cytology / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D008533:Megakaryocytes / Q000166:cytology* / Q000187:drug effects / Q000502:physiology* / Q000528:radiation effects; D051379:Mice; D008810:Mice, Inbred C57BL; D011833:Radiation Injuries, Experimental / Q000235:genetics / Q000473:pathology; D019718:Receptors, CXCR4 / Q000008:administration & dosage / Q000378:metabolism; D055153:Stem Cell Niche / Q000187:drug effects / Q000235:genetics* / Q000528:radiation effects; D034061:Thrombopoiesis / Q000187:drug effects / Q000235:genetics* / Q000528:radiation effects
chemical_list: D054377:Chemokine CXCL12; C515256:Cxcl12 protein, mouse; D019718:Receptors, CXCR4
references.citation: Blood. 2014 Jan 9;123(2):203-7
references.pmid: 24167196
references.citation: Radiat Res. 1971 Oct;48(1):107-15
references.pmid: 5117376
references.citation: Immunol Cell Biol. 2013 Jan;91(1):5-11
references.pmid: 23165606
references.citation: Proc Natl Acad Sci U S A. 1975 May;72(5):1744-8
references.pmid: 1098043
references.citation: Immunity. 2006 Dec;25(6):977-88
references.pmid: 17174120
references.citation: J Biol Chem. 2001 Aug 10;276(32):29839-45
references.pmid: 11390394
references.citation: Stem Cell Res. 2011 Nov;7(3):244-55
references.pmid: 21752744
references.citation: Nat Med. 2004 Aug;10(8):858-64
references.pmid: 15235597
references.citation: Blood. 2011 Aug 11;118(6):1516-24
references.pmid: 21673348
references.citation: Nat Immunol. 2005 Oct;6(10):1038-46
references.pmid: 16170318
references.citation: Am J Hematol. 1978;4(4):303-12
references.pmid: 717392
references.citation: Blood. 2006 Sep 1;108(5):1509-14
references.pmid: 16670270
references.citation: Blood. 2007 May 15;109(10):4237-44
references.pmid: 17234740
references.citation: J Thromb Haemost. 2008 Nov;6(11):1900-7
references.pmid: 18752571
references.citation: Nature. 1994 Jun 16;369(6481):568-71
references.pmid: 8202159
references.citation: Blood. 2011 Jan 13;117(2):429-39
references.pmid: 20833981
references.citation: Blood. 2005 Jul 15;106(2):505-13
references.pmid: 15817675
references.citation: Exp Hematol. 2011 May;39(5):580-590.e1
references.pmid: 21291952
references.citation: Stem Cells. 2013 Jan;31(1):137-45
references.pmid: 22961695
references.citation: Blood. 2000 Dec 15;96(13):4152-9
references.pmid: 11110686
references.citation: Br J Haematol. 1983 Feb;53(2):277-87
references.pmid: 6821656
references.citation: Mol Reprod Dev. 1995 Sep;42(1):19-27
references.pmid: 8562047
references.citation: Blood. 2009 Sep 10;114(11):2333-43
references.pmid: 19433859
references.citation: Stem Cells. 2002;20(4):320-8
references.pmid: 12110701
references.citation: Exp Hematol. 2007 Apr;35(4 Suppl 1):8-16
references.pmid: 17379081
references.citation: Biochim Biophys Acta. 2007 Apr;1768(4):952-63
references.pmid: 17169327
references.citation: Nature. 2005 Jun 16;435(7044):969-73
references.pmid: 15959517
references.citation: Blood. 1995 Aug 15;86(4):1331-8
references.pmid: 7632939
references.citation: Blood. 1968 Jul;32(1):102-10
references.pmid: 5690593
references.citation: Exp Hematol. 2011 Apr;39(4):434-45
references.pmid: 21291953
references.citation: Cell Stem Cell. 2009 Apr 3;4(4):313-23
references.pmid: 19341621
references.citation: Blood. 2002 Oct 15;100(8):2778-86
references.pmid: 12351385
references.citation: Blood. 2009 Dec 17;114(26):5404-6; author reply 5406-7
references.pmid: 20018929
references.citation: Cancer Res. 2005 Nov 1;65(21):9891-8
references.pmid: 16267013
references.citation: Proteomics. 2010 Dec;10(24):4342-51
references.pmid: 21136589
references.citation: Nature. 2013 Mar 14;495(7440):231-5
references.pmid: 23434755
references.citation: Nature. 2010 Aug 12;466(7308):829-34
references.pmid: 20703299
references.citation: Br J Haematol. 2000 Dec;111(3):879-89
references.pmid: 11122151
references.citation: Blood. 2007 Jun 1;109(11):4739-41
references.pmid: 17327409
references.citation: Dev Biol. 1999 Sep 15;213(2):442-56
references.pmid: 10479460
references.citation: J Immunol. 2002 Dec 15;169(12):7000-8
references.pmid: 12471135
references.citation: Blood. 2001 May 1;97(9):2587-95
references.pmid: 11313246
references.citation: Exp Hematol. 2002 Jun;30(6):513-28
references.pmid: 12063018
references.citation: Nat Cell Biol. 2013 May;15(5):533-43
references.pmid: 23624405
references.citation: Blood. 1994 Jul 1;84(1):10-9
references.pmid: 7517203
references.citation: Blood. 2011 Apr 28;117(17):4600-8
references.pmid: 21378272
references.citation: J Exp Med. 1998 Aug 3;188(3):539-48
references.pmid: 9687531
references.citation: Nature. 2013 Oct 31;502(7473):637-43
references.pmid: 24107994
references.citation: Blood. 2013 Jun 27;121(26):5238-49
references.pmid: 23667055
references.citation: Blood. 1999 Mar 1;93(5):1511-23
references.pmid: 10029579
references.citation: Blood. 1997 Feb 1;89(3):823-33
references.pmid: 9028313
references.citation: Stem Cells Dev. 2007 Jun;16(3):361-70
references.pmid: 17610366
references.citation: Blood Cells. 1989;15(1):3-14
references.pmid: 2649185
references.citation: Nature. 2013 Mar 14;495(7440):227-30
references.pmid: 23434756
references.citation: Nature. 1994 Jun 16;369(6481):533-8
references.pmid: 8202154
references.citation: Eur J Haematol. 2000 Mar;64(3):164-72
references.pmid: 10997882
references.citation: J Cell Biol. 1999 Dec 13;147(6):1299-312
references.pmid: 10601342
references.citation: Physiology (Bethesda). 2005 Oct;20:349-56
references.pmid: 16174874
references.citation: Radiat Res. 1961 Feb;14:213-22
references.pmid: 13776896
references.citation: J Antibiot (Tokyo). 1984 Apr;37(4):422-5
references.pmid: 6427168
references.citation: PLoS One. 2009 Dec 21;4(12):e8359
references.pmid: 20027303
references.citation: Br J Haematol. 2000 Mar;108(4):859-64
references.pmid: 10792296
references.citation: Blood. 2010 May 13;115(19):3886-94
references.pmid: 20009035
references.citation: Nat Med. 2004 Jan;10(1):64-71
references.pmid: 14702636
references.citation: Carbohydr Res. 2008 Aug 11;343(12):2018-23
references.pmid: 18334249
references.citation: J Clin Invest. 2000 Dec;106(11):1331-9
references.pmid: 11104786
references.citation: J Cell Biol. 1997 Nov 3;139(3):651-64
references.pmid: 9348282
references.citation: Br J Haematol. 1999 Feb;104(2):220-9
references.pmid: 10050701
references.citation: Blood Cells. 1991;17(3):527-49
references.pmid: 1760560
references.citation: Blood. 1998 Sep 1;92(5):1586-97
references.pmid: 9716586
references.citation: Blood. 2012 Sep 20;120(12):2501-11
references.pmid: 22889760
references.citation: Blood. 2007 Apr 1;109(7):2708-17
references.pmid: 17119115
references.citation: Blood. 2000 Feb 1;95(3):769-75
references.pmid: 10648384
references.citation: Blood. 1998 Aug 1;92(3):756-64
references.pmid: 9680341
references.citation: Braz J Med Biol Res. 2003 May;36(5):567-78
references.pmid: 12715075
references.citation: Stem Cells. 2013 Oct;31(10):2193-204
references.pmid: 23818291
references.citation: Blood. 2012 Oct 4;120(14):2787-95
references.pmid: 22653973
references.citation: Blood. 2004 Nov 15;104(10):3117-25
references.pmid: 15265786
references.citation: Cell Tissue Kinet. 1975 Nov;8(6):505-16
references.pmid: 1201580
references.citation: Clin Pharmacol Ther. 2004 Dec;76(6):628-38
references.pmid: 15592334
references.citation: Cell Stem Cell. 2009 Mar 6;4(3):263-74
references.pmid: 19265665
references.citation: Blood. 2010 Nov 4;116(18):3669-76
references.pmid: 20631377
references.citation: Blood. 1978 Jul;52(1):163-70
references.pmid: 656624
references.citation: Biochim Biophys Acta. 1991 Jan 29;1076(2):314-6
references.pmid: 1671823
references.citation: J Ultrastruct Res. 1969 Jan;26(1):111-29
references.pmid: 5775369
references.citation: Blood. 1984 Apr;63(4):917-20
references.pmid: 6367853
references.citation: Exp Hematol. 2004 Mar;32(3):300-7
references.pmid: 15003316
references.citation: Nat Med. 2012 Dec;18(12):1786-96
references.pmid: 23160239
references.citation: Blood. 1970 Jun;35(6):783-92
references.pmid: 5427248
references.citation: Methods Mol Med. 2005;105:289-302
references.pmid: 15492402
references.citation: Science. 2007 Sep 21;317(5845):1767-70
references.pmid: 17885137
references.citation: Cytometry A. 2014 Apr;85(4):302-12
references.pmid: 24616422