TY - JOUR
T1 - Fancd2-/- mice have hematopoietic defects that can be partially corrected by resveratrol
AU - Zhang, Qing-Shuo
AU - Marquez-Loza, Laura
AU - Eaton, Laura
AU - Duncan, Andrew W.
AU - Goldman, Devorah
AU - Anur, Praveen
AU - Watanabe-Smith, Kevin
AU - Rathbun, R. Keaney
AU - Fleming, William
AU - Bagby, Grover
AU - Grompe, Markus
PY - 2010/12/9
Y1 - 2010/12/9
N2 - 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 micro-environment, 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.
AB - 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 micro-environment, 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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U2 - 10.1182/blood-2010-04-278226
DO - 10.1182/blood-2010-04-278226
M3 - Article
C2 - 20826722
AN - SCOPUS:78650042041
SN - 0006-4971
VL - 116
SP - 5140
EP - 5148
JO - Blood
JF - Blood
IS - 24
ER -