The BET inhibitor CPI203 promotes ex vivo expansion of cord blood long-term repopulating HSCs and megakaryocytes.
The BET inhibitor CPI203 promotes ex vivo expansion of cord blood long-term repopulating HSCs and megakaryocytes.
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DOI：
10.1182/blood.2020005357
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发表时间：
2020-11-19
期刊：
影响因子：
20.3
通讯作者：
Watt SM
中科院分区：
文献类型：
--
作者：
Hua P;Hester J;Adigbli G;Li R;Psaila B;Roy A;Bataille CJR;Wynne GM;Jackson T;Milne TA;Russell AJ;Davies J;Roberts I;Issa F;Watt SM
尽管细胞因子介导的人造血干细胞（HSC）的膨胀可能导致造血祖细胞的高产量，但通常以降低骨髓HSC的重塑能力为代价，从而限制了潜在的治疗应用。由于已证明含溴决定域的蛋白质（BCP）来调节小鼠HSC自我更新和干性，因此我们筛选了针对各种BCP的小分子，作为人体HSC的实体扩张的潜在药物。在测试的10种化合物中，只有溴结构域和末端基序抑制剂CPI203增强了人索血液HSC的扩展，而不会在体外失去细胞活力。扩展的细胞还显示出在连续移植测定中改善的植入和重生。转录组和功能研究表明，长期重塑HSC的扩展伴随着同步扩展和与CPI203介导的脐带血造血干细胞和祖细胞的重编程一致的巨核细胞的成熟。因此，这种方法可能证明对离体基因编辑，增强血小板的产生以及改善脐带血用于移植研究和治疗的方法有益。 （血液2020; 136（21）：2410-2415）
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. (Blood. 2020;136(21):2410-2415)
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