期刊
BLOOD
卷 136, 期 21, 页码 2410-2415出版社
AMER SOC HEMATOLOGY
DOI: 10.1182/blood.2020005357
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资金
- MRC Discovery Award [MC_PC_15069]
- MRC Clinician Scientist Award [MR/R008108]
- KRUK Senior Fellowship
- Clarendon Scholarship
- Wellcome Trust CRCD Fellowships
- Bloodwise project grant
- Cancer Research UK Advanced Clinician Scientist Fellowship
- Medical Research Council Molecular Haematology Unit [MC_UU_12009/6]
- NIHR Oxford Biomedical Research Centre Haematology Theme
- MRC [MR/R008108/1, MC_UU_00016/6, MC_PC_15069] Funding Source: UKRI
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 ac-companied 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.
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