SIRT1 deficiency compromises mouse embryonic stem cell hematopoietic differentiation, and embryonic and adult hematopoiesis in the mouse

Abstract

SIRT1 is a founding member of a sirtuin family of 7 proteins and histone deacetylases. It is involved in cellular resistance to stress, metabolism, differentiation, aging, and tumor suppression. SIRT1-/- mice demonstrate embryonic and postnatal development defects. We examined hematopoietic and endothelial cell differentiation of SIRT1-/- mouse embryonic stem cells (ESCs) in vitro, and hematopoietic progenitors in SIRT1+/+, +/-, and -/- mice. SIRT1 -/- ESCs formed fewer mature blast cell colonies. Replated SIRT1 -/- blast colony-forming cells demonstrated defective hematopoietic potential. Endothelial cell production was unaltered, but there were defects in formation of a primitive vascular network from SIRT1-/--derived embryoid bodies. Development of primitive and definitive progenitors derived from SIRT1-/- ESCs were also delayed and/or defective. Differentiation delay/ defects were associated with delayed capacity to switch off Oct4, Nanog and Fgf5 expression, decreased β-H1 globin, β-major globin, and Scl gene expression, and reduced activation of Erk1/2. Ectopic expression of SIRT1 rescued SIRT1-/- ESC differentiation deficiencies. SIRT1-/- yolk sacs manifested fewer primitive erythroid precursors. SIRT1-/- and SIRT1+/- adult marrow had decreased numbers and cycling of hematopoietic progenitors, effects more apparent at 5%, than at 20%, oxygen tension, and these progenitors survived less well in vitro under conditions of delayed growth factor addition. This suggests a role for SIRT1 in ESC differentiation and mouse hematopoiesis.