The BET inhibitor CPI203 promotes ex vivo expansion of cord blood long-term repopulating HSCs and megakaryocytes.

Autor: Hua P; MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine.; Nuffield Division of Clinical Laboratory Medicine, Radcliffe Department of Medicine, University of Oxford., Hester J; Transplantation Research Immunology Group, Nuffield Department of Surgical Sciences, University of Oxford, and., Adigbli G; Transplantation Research Immunology Group, Nuffield Department of Surgical Sciences, University of Oxford, and., Li R; MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine., Psaila B; MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine., Roy A; Department of Paediatrics, University of Oxford, Children's Hospital, John Radcliffe Hospital, Oxford, United Kingdom., Bataille CJR; Department of Chemistry, University of Oxford, Chemistry Research Laboratory, and., Wynne GM; Department of Chemistry, University of Oxford, Chemistry Research Laboratory, and., Jackson T; Department of Paediatrics, University of Oxford, Children's Hospital, John Radcliffe Hospital, Oxford, United Kingdom., Milne TA; MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine., Russell AJ; Department of Chemistry, University of Oxford, Chemistry Research Laboratory, and.; Department of Pharmacology, University of Oxford, Oxford, United Kingdom; and., Davies J; MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine.; Nuffield Division of Clinical Laboratory Medicine, Radcliffe Department of Medicine, University of Oxford., Roberts I; MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine.; Department of Paediatrics, University of Oxford, Children's Hospital, John Radcliffe Hospital, Oxford, United Kingdom., Issa F; Transplantation Research Immunology Group, Nuffield Department of Surgical Sciences, University of Oxford, and., Watt SM; Nuffield Division of Clinical Laboratory Medicine, Radcliffe Department of Medicine, University of Oxford.; Adelaide Medical School, Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, Australia.
Jazyk: angličtina
Zdroj: Blood [Blood] 2020 Nov 19; Vol. 136 (21), pp. 2410-2415.
DOI: 10.1182/blood.2020005357
Abstrakt: Although cytokine-mediated expansion of human hematopoietic stem cells (HSCs) can result in high yields of hematopoietic progenitor cells, this generally occurs at the expense of reduced bone marrow HSC repopulating ability, thereby limiting potential therapeutic applications. Because bromodomain-containing proteins (BCPs) have been demonstrated to regulate mouse HSC self-renewal and stemness, we screened small molecules targeting various BCPs as potential agents for ex vivo expansion of human HSCs. Of 10 compounds tested, only the bromodomain and extra-terminal motif inhibitor CPI203 enhanced the expansion of human cord blood HSCs without losing cell viability in vitro. The expanded cells also demonstrated improved engraftment and repopulation in serial transplantation assays. Transcriptomic and functional studies showed that the expansion of long-term repopulating HSCs was accompanied by synchronized expansion and maturation of megakaryocytes consistent with CPI203-mediated reprogramming of cord blood hematopoietic stem and progenitor cells. This approach may therefore prove beneficial for ex vivo gene editing, for enhanced platelet production, and for the improved usage of cord blood for transplantation research and therapy.
(© 2020 by The American Society of Hematology.)
Databáze: MEDLINE