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

Xuan Ou, Hee Don Chae, Rui Hong Wang, William C. Shelley, Scott Cooper, Tammi Taylor, Young June Kim, Chu Xia Deng, Mervin C. Yoder, Hal E. Broxmeyer

Research output: Contribution to journalArticle

72 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)440-450
Number of pages11
JournalBlood
Volume117
Issue number2
DOIs
StatePublished - Jan 13 2011

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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