Identification of a potent small molecule capable of regulating polyploidization, megakaryocyte maturation, and platelet production.
Identification of a potent small molecule capable of regulating polyploidization, megakaryocyte maturation, and platelet production.
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DOI：
10.1186/s13045-016-0358-y
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发表时间：
2016-12-08
影响因子：
28.5
通讯作者：
Ma Y
中科院分区：
文献类型：
--
作者：
Huang N;Lou M;Liu H;Avila C;Ma Y
巨核细胞成熟涉及多倍化，巨核细胞 (MK) 倍性与其成熟和血小板产生相关。 MK 成熟迟缓与脐带血移植后 MK 植入不良和新生儿血小板减少症密切相关。尽管血小板减少症在影响婴儿和成人的一系列环境中患病率很高，但治疗方式仍然非常有限。从同意患者获得的脐带血或骨髓样本中分离出人类 CD34+ 细胞。使用 616452 培养和诱导细胞，并与市场上现有的药物（如 rominplostim 或 TPO）进行比较。使用碘化丙啶染色和流式细胞术分析完成倍性分析。动物研究包括将人类 CD34+ 细胞移植到 NOD.Cg-PrkdcscidIl2rgtm1Wjl/SzJ 小鼠中，然后每天注射 15 mg/kg 的 616452。在培养一周内，该化学物质能够诱导多倍体化，这是巨核细胞随着 DNA 含量积累而成熟所需的过程，达到 64 N 或更高，以达到相对成人的大小。我们观察到，与未诱导的细胞相比，16 N 或更大的细胞的倍数增加高达 200 倍，且呈剂量依赖性。此外，在 616452 存在下分化的 MK 表现出比用 rominplostim 培养的用于成人特发性血小板减少性紫癜 (ITP) 患者的 MK 更强大的 MK 分化能力。在移植人脐带血的小鼠中，616452 显着增强了骨髓中的 MK 重建和人外周血小板的产生。这种化学物质的分子治疗作用可能是通过 TPO 独立途径实现的。我们的研究可能对我们对胎儿 MK 生物学、血小板减少新生儿的临床管理和白血病分化治疗的基本理解产生重要影响。本文的在线版本 (doi:10.1186/s13045-016-0358-y) 包含补充材料，可供授权用户使用。
Megakaryocytic cell maturation involves polyploidization, and megakaryocyte (MK) ploidy correlates with their maturation and platelet production. Retardation of MK maturation is closely associated with poor MK engraftment after cord blood transplantation and neonatal thrombocytopenia. Despite the high prevalence of thrombocytopenia in a range of setting that affect infants to adults, there are still very limited modalities of treatment. Human CD34+ cells were isolated from cord blood or bone marrow samples acquired from consenting patients. Cells were cultured and induced using 616452 and compared to current drugs on the market such as rominplostim or TPO. Ploidy analysis was completed using propidium iodide staining and flow cytometry analysis. Animal studies consisted of transplanting human CD34+ cells into NOD.Cg-PrkdcscidIl2rgtm1Wjl/SzJ mice followed by daily injections of 15 mg/kg of 616452. Within one week of culture, the chemical was able to induce polyploidization, the process required for megakaryocyte maturation with the accumulation of DNA content, to 64 N or greater to achieve a relative adult size. We observed fold increases as high as 200-fold in cells of 16 N or greater compared to un-induced cells with a dose-dependent manner. In addition, MK differentiated in the presence of 616452 demonstrated a more robust capacity of MK differentiation than that of MKs cultured with rominplostim used for adult idiopathic thrombocytopenic purpura (ITP) patients. In mice transplanted with human cord blood, 616452 strikingly enhanced MK reconstitution in the marrow and human peripheral platelet production. The molecular therapeutic actions for this chemical may be through TPO-independent pathways. Our studies may have an important impact on our fundamental understanding of fetal MK biology, the clinical management of thrombocytopenic neonates and leukemic differentiation therapy. The online version of this article (doi:10.1186/s13045-016-0358-y) contains supplementary material, which is available to authorized users.
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影响因子：
2.4
作者：
von Lindern JS;van den Bruele T;Lopriore E;Walther FJ
通讯作者：
Walther FJ
影响因子：
28.5
作者：
Jeong JY;Levine MS;Abayasekara N;Berliner N;Laubach J;Vanasse GJ
通讯作者：
Vanasse GJ
影响因子：
20.3
作者：
Aguila, Jerell R.;Liao, Wenbin;Ma, Yupo
通讯作者：
Ma, Yupo
影响因子：
4.3
作者：
Ignatz, Mark;Sola-Visner, Martha;Slayton, William B.
通讯作者：
Slayton, William B.
DOI：
10.1002/stem.5530080405
发表时间：
1990-07-01
期刊：
INTERNATIONAL JOURNAL OF CELL CLONING
影响因子：
--
作者：
JACKSON, CW
通讯作者：
JACKSON, CW