title: Fancd2-/- mice have hematopoietic defects that can be partially corrected by resveratrol.
abstract: 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.
authors.affiliation: Oregon Stem Cell Center, Department of Pediatrics, Oregon Health & Science University, Portland, OR, USA. zhangqi@ohsu.edu
authors.forename: Qing-Shuo
authors.initials: QS
authors.lastname: Zhang
authors.forename: Laura
authors.initials: L
authors.lastname: Marquez-Loza
authors.forename: Laura
authors.initials: L
authors.lastname: Eaton
authors.forename: Andrew W
authors.initials: AW
authors.lastname: Duncan
authors.forename: Devorah C
authors.initials: DC
authors.lastname: Goldman
authors.forename: Praveen
authors.initials: P
authors.lastname: Anur
authors.forename: Kevin
authors.initials: K
authors.lastname: Watanabe-Smith
authors.forename: R Keaney
authors.initials: RK
authors.lastname: Rathbun
authors.forename: William H
authors.initials: WH
authors.lastname: Fleming
authors.forename: Grover C
authors.initials: GC
authors.lastname: Bagby
authors.forename: Markus
authors.initials: M
authors.lastname: Grompe
mesh_terms: 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
chemical_list: D000975:Antioxidants; C499904:Fancd2 protein, mouse; D052236:Fanconi Anemia Complementation Group D2 Protein; D013267:Stilbenes; D000077185:Resveratrol
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