Evidence that growth factor independence 1b regulates dormancy and peripheral blood mobilization of hematopoietic stem cells.
Donor-matched transplantation of hematopoietic stem cells (HSCs) is widely used to treat hematologic malignancies but is associated with high mortality. The expansion of HSC numbers and their mobilization into the bloodstream could significantly improve therapy. We report here that adult mice conditionally deficient for the transcription Growth factor independence 1b (Gfi1b) show a significant expansion of functional HSCs in the bone marrow and blood. Despite this expansion, Gfi1b(ko/ko) HSCs retain their ability to self-renew and to initiate multilineage differentiation but are no longer quiescent and contain elevated levels of reactive oxygen species. Treatment of Gfi1b(ko/ko) mice with N-acetyl-cystein significantly reduced HSC numbers indicating that increased reactive oxygen species levels are at least partially responsible for the expansion of Gfi1b-deficient HSCs. Moreover, Gfi1b(-/-) HSCs show decreased expression of CXCR4 and Vascular cell adhesion protein-1, which are required to retain dormant HSCs in the endosteal niche, suggesting that Gfi1b regulates HSC dormancy and pool size without affecting their function. Finally, the additional deletion of the related Gfi1 gene in Gfi1b(ko/ko) HSCs is incompatible with the maintenance of HSCs, suggesting that Gfi1b and Gfi1 have partially overlapping functions but that at least one Gfi gene is essential for the generation of HSCs.
Khandanpour
Cyrus
C
Institut de recherches cliniques de Montréal, Canada.
Sharif-Askari
Ehssan
E
Vassen
Lothar
L
Gaudreau
Marie-Claude
MC
Zhu
Jinfang
J
Paul
William E
WE
Okayama
Taro
T
Kosan
Christian
C
Möröy
Tarik
T
D000111:Acetylcysteine / Q000494:pharmacology; D006631:Amine Oxidase (Copper-Containing) / Q000096:biosynthesis; D000818:Animals; D015815:Cell Adhesion Molecules / Q000096:biosynthesis; D002465:Cell Movement; D004268:DNA-Binding Proteins / Q000502:physiology; D006412:Hematopoietic Stem Cells / Q000166:cytology*; D006706:Homeostasis; D051379:Mice; D018345:Mice, Knockout; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000502:physiology*; D017382:Reactive Oxygen Species; D019718:Receptors, CXCR4 / Q000096:biosynthesis; D012097:Repressor Proteins / Q000172:deficiency / Q000502:physiology*; D014157:Transcription Factors / Q000502:physiology
C514936:CXCR4 protein, mouse; D015815:Cell Adhesion Molecules; D004268:DNA-Binding Proteins; C079873:Gfi1 protein, mouse; C486395:Gfi1b protein, mouse; D011518:Proto-Oncogene Proteins; D017382:Reactive Oxygen Species; D019718:Receptors, CXCR4; D012097:Repressor Proteins; D014157:Transcription Factors; D006631:Amine Oxidase (Copper-Containing); C492678:semicarbazide-sensitive amine oxidase-vascular adhesion protein-1, mouse; D000111:Acetylcysteine
J Exp Med. 2008 Apr 14;205(4):777-83
18378795
Curr Opin Cell Biol. 2006 Oct;18(5):482-90
16919433
Int J Biochem Cell Biol. 2005 Mar;37(3):541-6
15618011
Nature. 2004 Oct 21;431(7011):1002-7
15457180
Curr Opin Hematol. 2006 Jan;13(1):1-6
16319680
Cell. 2008 Feb 22;132(4):631-44
18295580
Blood. 2008 Dec 15;112(13):4793-807
19064739
Cell Stem Cell. 2007 Nov;1(5):541-54
18345353
Nature. 2009 Jan 1;457(7225):97-101
19052548
Nat Med. 2006 Apr;12(4):446-51
16565722
Ann N Y Acad Sci. 2007 Jun;1106:41-53
17332071
Curr Opin Genet Dev. 2009 Oct;19(5):461-8
19811902
Blood. 2010 Jan 21;115(3):687-95
19965638
Ann Hematol. 2010 Aug;89(8):759-65
20143233
Haematologica. 2010 Jan;95(1):36-46
19773260
Nat Rev Immunol. 2006 Feb;6(2):93-106
16491134
N Engl J Med. 2006 Apr 27;354(17):1813-26
16641398
Mol Cell. 2007 Aug 17;27(4):562-72
17707228
Genes Dev. 2002 Feb 1;16(3):301-6
11825872
Nat Biotechnol. 2009 Jan;27(1):84-90
19060879
Cell. 2005 Apr 22;121(2):295-306
15851035
Cell. 2008 Dec 12;135(6):1118-29
19062086
Blood. 2007 Oct 1;110(7):2276-85
17596540
Genes Dev. 2007 Dec 1;21(23):3044-60
18056420
Nature. 2009 Apr 16;458(7240):904-8
19212321
Nucleic Acids Res. 2004 May 06;32(8):2508-19
15131254
Blood. 2010 Apr 8;115(14):2784-95
20124515
Immunol Rev. 2008 Jun;223:236-51
18613840
Cell. 2005 Jul 1;121(7):1109-21
15989959
EMBO J. 2004 Oct 13;23(20):4116-25
15385956
Nucleic Acids Res. 2005 Feb 17;33(3):987-98
15718298
Cell Stem Cell. 2009 Jan 9;4(1):37-48
19128791
Science. 1996 Jul 12;273(5272):242-5
8662508
Curr Opin Genet Dev. 2006 Oct;16(5):496-501
16919448
Science. 2001 Nov 30;294(5548):1933-6
11729320
Nature. 2008 May 8;453(7192):228-32
18418377
Haematologica. 2009 Nov;94(11):1477-81
19880773
Curr Opin Hematol. 2010 Jul;17(4):300-7
20571393
Blood. 2002 Oct 15;100(8):2769-77
12351384
Nat Rev Immunol. 2008 Apr;8(4):290-301
18323850
Blood. 2007 Mar 15;109(6):2356-64
17095621
J Exp Med. 2010 Jun 7;207(6):1173-82
20421392
Nat Rev Mol Cell Biol. 2007 Sep;8(9):703-13
17717515
Blood. 2005 Feb 15;105(4):1448-55
15507521
Nucleic Acids Res. 2004 Jul 27;32(13):3935-46
15280509
J Cell Physiol. 2010 Jan;222(1):17-22
19725055
Curr Opin Hematol. 2009 Jul;16(4):255-8
19465850
J Biol Chem. 2004 Sep 24;279(39):40906-17
15252036
Proc Natl Acad Sci U S A. 2006 Nov 28;103(48):18214-9
17116877
Nature. 2009 Jan 1;457(7225):92-6
19052546