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.
ASJC Scopus subject areas
- Cell Biology