Fancd2-/- mice have hematopoietic defects that can be partially corrected by resveratrol.
Progressive bone marrow failure is a major cause of morbidity and mortality in human Fanconi Anemia patients. In an effort to develop a Fanconi Anemia murine model to study bone marrow failure, we found that Fancd2(-/-) mice have readily measurable hematopoietic defects. Fancd2 deficiency was associated with a significant decline in the size of the c-Kit(+)Sca-1(+)Lineage(-) (KSL) pool and reduced stem cell repopulation and spleen colony-forming capacity. Fancd2(-/-) KSL cells showed an abnormal cell cycle status and loss of quiescence. In addition, the supportive function of the marrow microenvironment was compromised in Fancd2(-/-) mice. Treatment with Sirt1-mimetic and the antioxidant drug, resveratrol, maintained Fancd2(-/-) KSL cells in quiescence, improved the marrow microenvironment, partially corrected the abnormal cell cycle status, and significantly improved the spleen colony-forming capacity of Fancd2(-/-) bone marrow cells. We conclude that Fancd2(-/-) mice have readily quantifiable hematopoietic defects, and that this model is well suited for pharmacologic screening studies.
Zhang
Qing-Shuo
QS
Oregon Stem Cell Center, Department of Pediatrics, Oregon Health & Science University, Portland, OR, USA. zhangqi@ohsu.edu
Marquez-Loza
Laura
L
Eaton
Laura
L
Duncan
Andrew W
AW
Goldman
Devorah C
DC
Anur
Praveen
P
Watanabe-Smith
Kevin
K
Rathbun
R Keaney
RK
Fleming
William H
WH
Bagby
Grover C
GC
Grompe
Markus
M
D000818:Animals; D000975:Antioxidants; D001853:Bone Marrow / Q000187:drug effects; D002453:Cell Cycle; D019070:Cell Lineage; D003114:Colony-Forming Units Assay; D005199:Fanconi Anemia / Q000188:drug therapy*; D052236:Fanconi Anemia Complementation Group D2 Protein / Q000172:deficiency* / Q000235:genetics; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects; D006413:Hematopoietic System / Q000187:drug effects*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D000077185:Resveratrol; D013154:Spleen / Q000166:cytology; D013267:Stilbenes / Q000494:pharmacology* / Q000627:therapeutic use; D016896:Treatment Outcome
D000975:Antioxidants; C499904:Fancd2 protein, mouse; D052236:Fanconi Anemia Complementation Group D2 Protein; D013267:Stilbenes; D000077185:Resveratrol
J Nutr. 2002 Jul;132(7):2076-81
12097696
Mutat Res. 2009 Jul 31;668(1-2):141-9
19508850
Nature. 2004 Oct 21;431(7011):1002-7
15457180
Fetal Diagn Ther. 2006;21(1):118-24
16354989
Nature. 1981 Mar 12;290(5802):142-3
7207594
Am J Hematol. 1993 Feb;42(2):196-201
8438880
Blood. 2003 Feb 15;101(4):1249-56
12393516
Blood. 1994 Mar 1;83(5):1216-25
8118026
Exp Neurol. 2010 Jul;224(1):325-9
20381489
Blood. 2009 Dec 17;114(26):5290-8
19850743
Nature. 2007 Nov 29;450(7170):712-6
18046409
Genes Dev. 2003 Aug 15;17(16):2021-35
12893777
Annu Rev Genet. 2009;43:223-49
19686080
Nature. 2003 Sep 11;425(6954):191-6
12939617
EMBO J. 2005 Feb 23;24(4):861-71
15692571
Blood. 1997 Aug 1;90(3):974-85
9242526
Cell. 2008 Nov 28;135(5):907-18
19041753
PLoS One. 2008 Apr 16;3(4):e2020
18414679
Semin Hematol. 2006 Jul;43(3):147-56
16822457
Cancer Cell. 2008 Oct 7;14(4):312-23
18835033
Nat Med. 2004 Jul;10(7):744-8
15195088
J Cell Sci. 2007 May 1;120(Pt 9):1572-83
17405815
Nat Rev Genet. 2008 Feb;9(2):115-28
18202695
Blood. 2006 Jun 1;107(11):4223-33
16493006
J Immunol. 2007 Apr 15;178(8):5277-87
17404312
Nature. 2009 Jul 30;460(7255):587-91
19641587
Cancer Res. 2008 Mar 1;68(5):1601-8
18316625
Nat Rev Genet. 2007 Oct;8(10):735-48
17768402
Nature. 2007 Jun 7;447(7145):725-9
17554309
Nature. 2006 May 25;441(7092):518-22
16633340
Acta Haematol. 2002;108(4):231-6
12432219
Mol Cell. 2001 Feb;7(2):241-8
11239453
Cell Stem Cell. 2007 Nov;1(5):578-91
18371395
Cell Stem Cell. 2007 Jun 7;1(1):113-26
18371340
Blood. 2003 Sep 15;102(6):2053-9
12750172
Arch Med Res. 2010 May;41(4):288-94
20637373
Transfusion. 1990 Oct;30(8):682-7
2219253
Am J Hum Genet. 2007 May;80(5):895-910
17436244
Blood. 2009 Mar 5;113(10):2342-51
19129541
Antioxid Redox Signal. 2008 Nov;10(11):1909-21
18627348
Cell. 2005 Feb 25;120(4):473-82
15734680
Biochem J. 2006 Aug 1;397(3):519-27
16626303
Blood. 1999 Jul 1;94(1):1-8
10381491
Exp Hematol. 1999 Nov;27(11):1667-74
10560914
Blood. 1999 Sep 15;94(6):2151-8
10477746
Dev Cell. 2003 Dec;5(6):903-14
14667412
Genes Dev. 2004 Nov 15;18(22):2747-63
15545632
J Clin Invest. 2007 Nov;117(11):3283-95
17960249
Blood. 2004 Aug 15;104(4):1204-9
15113761