Ricolinostat promotes the generation of megakaryocyte progenitors from human hematopoietic stem and progenitor cells.
Ricolinostat promotes the generation of megakaryocyte progenitors from human hematopoietic stem and progenitor cells.
复制标题
利可林司他促进人类造血干细胞和祖细胞产生巨核细胞祖细胞
DOI：
10.1186/s13287-022-02722-5
复制
发表时间：
2022-02-05
影响因子：
7.5
通讯作者：
Li Y
中科院分区：
文献类型：
--
作者：
Jiang J;Qin J;Li J;Lin X;Zhang B;Fan Z;He L;Zeng Q;Yue W;Zheng M;Pei X;Li Y
背景从干细胞离体产生诱导巨核细胞（MK）和血小板是提供可输注血小板的另一种方法。然而，从造血干细胞和祖细胞（HSPC）中产生大量MK和血小板是很困难的。方法为了优化HSPC向巨核细胞的分化效率，我们首先采用血小板因子4（PF4）启动子报告基因和高通量筛选策略来筛选小分子。我们还研究了候选小分子对人HSPC巨核细胞分化的影响和可能的机制。结果小分子Ricolinostat显着促进巨核细胞系中PF4启动子报告基因的表达。值得注意的是，基于细胞表面标志物检测、集落形成单位-MK 测定和定量实时 PCR 分析，Ricolinostat 显着增强了来自脐带血 HSPC 的 MK 祖细胞 (MkP) 的细胞命运承诺，并促进了 MkP 的增殖。 利可林司他诱导的 HSPC 产生的 MkP 分化为成熟的 MK 和血小板。从机制上讲，我们发现Ricolinostat主要通过抑制IL-8的分泌和降低IL-8受体CXCR2的表达来增强MkP的命运。结论在培养基中添加Ricolinostat主要通过抑制IL-8/CXCR2途径促进MkP从HSPC的分化并增强MkP的增殖。我们的结果可以帮助开发生产方案，以在体外从干细胞中有效生成 MK 和血小板。
BackgroundEx vivo production of induced megakaryocytes (MKs) and platelets from stem cells is an alternative approach for supplying transfusible platelets. However, it is difficult to generate large numbers of MKs and platelets from hematopoietic stem cells and progenitor cells (HSPCs).MethodsTo optimize the differentiation efficiency of megakaryocytic cells from HSPCs, we first employed a platelet factor 4 (PF4)-promoter reporter and high-throughput screening strategy to screen for small molecules. We also investigated the effects and possible mechanisms of candidate small molecules on megakaryocytic differentiation of human HSPCs.ResultsThe small molecule Ricolinostat remarkably promoted the expression of PF4-promoter reporter in the megakaryocytic cell line. Notably, Ricolinostat significantly enhanced the cell fate commitment of MK progenitors (MkPs) from cord blood HSPCs and promoted the proliferation of MkPs based on cell surface marker detection, colony-forming unit-MK assay, and quantitative real-time PCR analyses. MkPs generated from Ricolinostat-induced HSPCs differentiated into mature MKs and platelets. Mechanistically, we found that Ricolinostat enhanced MkP fate mainly by inhibiting the secretion of IL-8 and decreasing the expression of the IL-8 receptor CXCR2.ConclusionThe addition of Ricolinostat to the culture medium promoted MkP differentiation from HSPCs and enhanced the proliferation of MkPs mainly by suppressing the IL-8/CXCR2 pathway. Our results can help the development of manufacturing protocols for the efficient generation of MKs and platelets from stem cells in vitro.
登录
查看更多内容
影响因子：
6
作者：
Guan X;Qin M;Zhang Y;Wang Y;Shen B;Ren Z;Ding X;Dai W;Jiang Y
通讯作者：
Jiang Y
影响因子：
20.3
作者：
GEWIRTZ, AM;ZHANG, J;PONCZ, M
通讯作者：
PONCZ, M
影响因子：
20.3
作者：
Emadi, S;Clay, D;Le Bousse-Kerdilès, MC
通讯作者：
Le Bousse-Kerdilès, MC
DOI：
10.1016/j.ijbiomac.2021.02.131
发表时间：
2021-02-24
影响因子：
8.2
作者：
Fathi, Ezzatollah;Farahzadi, Raheleh;Valipour, Behnaz
通讯作者：
Valipour, Behnaz
影响因子：
4.6
作者：
Frei JC;Nyakatura EK;Zak SE;Bakken RR;Chandran K;Dye JM;Lai JR
通讯作者：
Lai JR