Fancd2-/- mice have hematopoietic defects that can be partially corrected by resveratrol

Oregon Stem Cell Center, Department of Pediatrics, Oregon Health & Science University, Portland, OR, USA.
Blood (Impact Factor: 10.45). 12/2010; 116(24):5140-8. DOI: 10.1182/blood-2010-04-278226
Source: PubMed


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.

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Available from: Qingshuo Zhang, Jan 12, 2015
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    • "Bone marrow cells were isolated from the femora and tibiae of the mice and stained as described previously (Zhang et al., 2010). The KSL antibody cocktail contains anti-mouse c-Kit, Sca-1, and lineage markers (CD3e, CD4, CD5, CD8a, B220, Ter119, NK1.1, Mac1, Gr1). "

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    • "Fancd2 À/À mice and controls were given either OXM diet or placebo for 4 months starting at 1 month of age. We previously reported that Fancd2 À/À KSL cells lose quiescence and display enhanced cell cycle entry (Zhang et al., 2010, 2013). Four months of OXM therapy were insufficient to change the size of HSPC pool or affect HSPC function in the colony-forming unit-spleen assay (data not shown). "
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    ABSTRACT: Androgens are widely used for treating Fanconi anemia (FA) and other human bone marrow failure syndromes, but their mode of action remains incompletely understood. Aged Fancd2(-/-) mice were used to assess the therapeutic efficacy of oxymetholone (OXM) and its mechanism of action. Eighteen-month-old Fancd2(-/-) mice recapitulated key human FA phenotypes, including reduced bone marrow cellularity, red cell macrocytosis, and peripheral pancytopenia. As in humans, chronic OXM treatment significantly improved these hematological parameters and stimulated the proliferation of hematopoietic stem and progenitor cells. RNA-Seq analysis implicated downregulation of osteopontin as an important potential mechanism for the drug's action. Consistent with the increased stem cell proliferation, competitive repopulation assays demonstrated that chronic OXM therapy eventually resulted in stem cell exhaustion. These results expand our knowledge of the regulation of hematopoietic stem cell proliferation and have direct clinical implications for the treatment of bone marrow failure. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Stem Cell Reports 11/2014; 4(1). DOI:10.1016/j.stemcr.2014.10.014 · 5.37 Impact Factor
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    • "Zhang et al. HSC repopulating capacity, and abnormal cell cycle status of KSL cells (loss of quiescence and increased cycling) (Zhang et al., 2010). To determine whether lack of p21 has an impact on any of these parameters in Fancd2 −/− mice, we characterized hematopoietic phenotypes of Fancd2 −/− "
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    ABSTRACT: Fanconi anemia patients suffer from progressive bone marrow failure. An overactive p53 response to DNA damage contributes to the progressive elimination of Fanconi anemia hematopoietic stem and progenitor cells (HSPC), and hence presents a potential target for therapeutic intervention. To investigate whether the cell cycle regulatory protein p21 is the primary mediator of the p53-dependent stem cell loss, p21/Fancd2 double-knockout mice were generated. Surprisingly double mutant mice displayed even more severe loss of HSPCs than Fancd2(-/-) single mutants. p21 deletion did not rescue the abnormal cell cycle profile and had no impact on the long-term repopulating potential of Fancd2(-/-) bone marrow cells. Collectively, our data indicate that p21 has an indispensable role in maintaining a normal HSPC pool and suggest that other p53-targeted factors, not p21, mediate the progressive elimination of HSPC in Fanconi anemia.
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