The Sirt1 activator SRT3025 expands hematopoietic stem and progenitor cells and improves hematopoiesis in Fanconi anemia mice

Qing-Shuo Zhang, Matthew Deater, Kathryn Schubert, Laura Marquez-Loza, Carl Pelz, David A. Sinclair, Markus Grompe

Research output: Contribution to journalArticle

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Abstract

Fanconi anemia is a genetic bone marrow failure syndrome. The current treatment options are suboptimal and do not prevent the eventual onset of aplastic anemia requiring bone marrow transplantation. We previously showed that resveratrol, an antioxidant and an activator of the protein deacetylase Sirt1, enhanced hematopoiesis in Fancd2 mutant mice and improved the impaired stem cell quiescence observed in this disease. Given that Sirt1 is important for the function of hematopoietic stem cells, we hypothesized that Sirt1 activation may improve hematopoiesis. Indeed, Fancd2-/- mice and wild-type mice treated with the selective Sirt1 activator SRT3025 had increased numbers of hematopoietic stem and progenitor cells, platelets and white blood cells. SRT3025 was also protective against acetaldehyde-induced hematopoietic damage. Unlike resveratrol, however, SRT3025 did not affect stem cell quiescence, suggesting distinct mechanisms of action. Conditional deletion of Sirt1 in hematopoietic cells did not abrogate the beneficial effects of SRT3025, indicating that the drug did not act by directly stimulating Sirt1 in stem cells, but must be acting indirectly via extra-hematopoietic effects. RNA-Seq transcriptome analysis revealed the down-regulation of Egr1-p21 expression, providing a potential mechanism for improved hematopoiesis. Overall, our data indicate that SRT3025 or related compounds may be beneficial in Fanconi anemia and other bone marrow failure syndromes.

Original languageEnglish (US)
Pages (from-to)130-140
Number of pages11
JournalStem Cell Research
Volume15
Issue number1
DOIs
StatePublished - Jul 1 2015

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Fanconi Anemia
Hematopoiesis
Hematopoietic Stem Cells
Stem Cells
Acetaldehyde
Aplastic Anemia
Gene Expression Profiling
Bone Marrow Transplantation
Leukocytes
Blood Platelets
Down-Regulation
Antioxidants
SRT3025
RNA
Pharmaceutical Preparations
Proteins

ASJC Scopus subject areas

  • Cell Biology
  • Developmental Biology
  • Medicine(all)

Cite this

The Sirt1 activator SRT3025 expands hematopoietic stem and progenitor cells and improves hematopoiesis in Fanconi anemia mice. / Zhang, Qing-Shuo; Deater, Matthew; Schubert, Kathryn; Marquez-Loza, Laura; Pelz, Carl; Sinclair, David A.; Grompe, Markus.

In: Stem Cell Research, Vol. 15, No. 1, 01.07.2015, p. 130-140.

Research output: Contribution to journalArticle

Zhang, Qing-Shuo ; Deater, Matthew ; Schubert, Kathryn ; Marquez-Loza, Laura ; Pelz, Carl ; Sinclair, David A. ; Grompe, Markus. / The Sirt1 activator SRT3025 expands hematopoietic stem and progenitor cells and improves hematopoiesis in Fanconi anemia mice. In: Stem Cell Research. 2015 ; Vol. 15, No. 1. pp. 130-140.
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