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

• Published in: Blood 2011-01, Vol.117 (2), p.440-450
• Main Authors: Ou, Xuan, Chae, Hee-Don, Wang, Rui-Hong, Shelley, William C., Cooper, Scott, Taylor, Tammi, Kim, Young-June, Deng, Chu-Xia, Yoder, Mervin C., Broxmeyer, Hal E.
• Format: Article
• Language: English
• Subjects: Aging; Animals; Biological and medical sciences; Blotting, Western; Cell Separation; Embryonic Stem Cells - cytology; Embryonic Stem Cells - metabolism; Flow Cytometry; Gene Expression; Gene Expression Regulation, Developmental - physiology; Hematologic and hematopoietic diseases; Hematopoiesis - physiology; Hematopoiesis and Stem Cells; Hematopoietic Stem Cells - cytology; Hematopoietic Stem Cells - metabolism; Immunohistochemistry; Medical sciences; Mice; Mice, Knockout; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction; Sirtuin 1 - deficiency; Sirtuin 1 - genetics; Sirtuin 1 - metabolism
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2010-03-273011

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.