title: Nicotinamide, a SIRT1 inhibitor, inhibits differentiation and facilitates expansion of hematopoietic progenitor cells with enhanced bone marrow homing and engraftment.
abstract: Strategies that increase homing to the bone marrow and engraftment efficacy of ex vivo expended CD34(+) cells are expected to enhance their clinical utility. Here we report that nicotinamide (NAM), a form of vitamin B-3, delayed differentiation and increased engraftment efficacy of cord blood-derived human CD34(+) cells cultured with cytokines. In the presence of NAM, the fraction of CD34(+)CD38(-) cells increased and the fraction of differentiated cells (CD14(+), CD11b(+), and CD11c(+)) decreased. CD34(+) cells cultured with NAM displayed increased migration toward stromal cell derived factor-1 and homed to the bone marrow with higher efficacy, thus contributing to their increased engraftment efficacy, which was maintained in competitive transplants with noncultured competitor cells. NAM is a known potent inhibitor of several classes of ribosylase enzymes that require NAD for their activity, as well as sirtuin (SIRT1), class III NAD(+)-dependent-histone-deacetylase. We demonstrated that EX-527, a specific inhibitor of SIRT1 catalytic activity, inhibited differentiation of CD34(+) cells similar to NAM, while specific inhibitors of NAD-ribosylase enzymes did not inhibit differentiation, suggesting that the NAM effect is SIRT1-specific. Our findings suggest a critical function of SIRT1 in the regulation of hematopoietic stem cell activity and imply the clinical utility of NAM for ex vivo expansion of functional CD34(+) cells.
authors.affiliation: Gamida Cell Ltd., Jerusalem, Israel. Tony@gamida-cell.com
authors.forename: Tony
authors.initials: T
authors.lastname: Peled
authors.forename: Hadas
authors.initials: H
authors.lastname: Shoham
authors.forename: Dorit
authors.initials: D
authors.lastname: Aschengrau
authors.forename: Dima
authors.initials: D
authors.lastname: Yackoubov
authors.forename: Gabi
authors.initials: G
authors.lastname: Frei
authors.forename: Noga
authors.initials: N
authors.lastname: Rosenheimer G
authors.forename: Batya
authors.initials: B
authors.lastname: Lerrer
authors.forename: Haim Y
authors.initials: HY
authors.lastname: Cohen
authors.forename: Arnon
authors.initials: A
authors.lastname: Nagler
authors.forename: Eitan
authors.initials: E
authors.lastname: Fibach
authors.forename: Amnon
authors.initials: A
authors.lastname: Peled
mesh_terms: D036002:ADP Ribose Transferases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D001854:Bone Marrow Cells; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured / Q000166:cytology / Q000187:drug effects; D054377:Chemokine CXCL12 / Q000494:pharmacology; D003114:Colony-Forming Units Assay; D005312:Fetal Blood / Q000166:cytology; D006085:Graft Survival; D006410:Hematopoiesis / Q000187:drug effects*; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects*; D006801:Humans; D016130:Immunophenotyping; D007231:Infant, Newborn; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009536:Niacinamide / Q000494:pharmacology*; D011828:Radiation Chimera; D019718:Receptors, CXCR4 / Q000096:biosynthesis / Q000235:genetics; D056564:Sirtuin 1 / Q000037:antagonists & inhibitors / Q000502:physiology*
chemical_list: C527276:CXCR4 protein, human; D054377:Chemokine CXCL12; D019718:Receptors, CXCR4; D009536:Niacinamide; D036002:ADP Ribose Transferases; C447939:SIRT1 protein, human; D056564:Sirtuin 1