title: The Sirt1 activator SRT3025 expands hematopoietic stem and progenitor cells and improves hematopoiesis in Fanconi anemia mice.
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.
authors.affiliation: Oregon Stem Cell Center, Department of Pediatrics, Oregon Health & Science University, Portland, OR 97239, USA. Electronic address: zhangqi@ohsu.edu.
authors.forename: Qing-Shuo
authors.initials: QS
authors.lastname: Zhang
authors.affiliation: Oregon Stem Cell Center, Department of Pediatrics, Oregon Health & Science University, Portland, OR 97239, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Deater
authors.affiliation: Oregon Stem Cell Center, Department of Pediatrics, Oregon Health & Science University, Portland, OR 97239, USA.
authors.forename: Kathryn
authors.initials: K
authors.lastname: Schubert
authors.affiliation: Oregon Stem Cell Center, Department of Pediatrics, Oregon Health & Science University, Portland, OR 97239, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Marquez-Loza
authors.affiliation: Oregon Stem Cell Center, Department of Pediatrics, Oregon Health & Science University, Portland, OR 97239, USA.
authors.forename: Carl
authors.initials: C
authors.lastname: Pelz
authors.affiliation: Paul F. Glenn Laboratories for the Biological Mechanisms of Aging, Department of Genetics, Harvard Medical School, Boston, MA 02115, USA; Department of Pharmacology, Medicine, The University of New South Wales, Sydney, NSW 2052, Australia.
authors.forename: David A
authors.initials: DA
authors.lastname: Sinclair
authors.affiliation: Oregon Stem Cell Center, Department of Pediatrics, Oregon Health & Science University, Portland, OR 97239, USA.
authors.forename: Markus
authors.initials: M
authors.lastname: Grompe
mesh_terms: D000079:Acetaldehyde; D000813:Anilides / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D001772:Blood Cell Count; D049109:Cell Proliferation / Q000187:drug effects; D004032:Diet; D000431:Ethanol / Q000494:pharmacology; D005199:Fanconi Anemia / Q000097:blood / Q000473:pathology*; D017353:Gene Deletion; D020869:Gene Expression Profiling; D006410:Hematopoiesis / Q000187:drug effects*; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D008822:Mice, Transgenic; D017423:Sequence Analysis, RNA; D056564:Sirtuin 1 / Q000378:metabolism*; D013844:Thiazoles / Q000008:administration & dosage / Q000494:pharmacology*; D059467:Transcriptome / Q000187:drug effects / Q000235:genetics
chemical_list: D000813:Anilides; C000601293:SRT3025; D013844:Thiazoles; D000431:Ethanol; D056564:Sirtuin 1; D000079:Acetaldehyde