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

X Ou, HD Chae, RH Wang, WC Shelley… - Blood, The Journal …, 2011 - ashpublications.org
X Ou, HD Chae, RH Wang, WC Shelley, S Cooper, T Taylor, YJ Kim, CX Deng, MC Yoder
Blood, The Journal of the American Society of Hematology, 2011ashpublications.org
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 …
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.
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