Application of small molecule CHIR99021 leads to the loss of hemangioblast progenitor and increased hematopoiesis of human pluripotent stem cells
Application of small molecule CHIR99021 leads to the loss of hemangioblast progenitor and increased hematopoiesis of human pluripotent stem cells
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DOI：
10.1016/j.exphem.2018.05.007
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发表时间：
2018-09-01
影响因子：
2.6
通讯作者：
Galat, Vasiliy
中科院分区：
文献类型：
--
作者：
Galat, Yekaterina;Elcheva, Irina;Galat, Vasiliy
提高我们对诱导或胚胎人类多能干细胞造血功能的复杂性的理解对许多研究领域和转化医学都是有益的。目前，尚不清楚在人多能干细胞体外造血分化过程中，最终祖细胞的成熟是通过原始祖细胞（成血管细胞）中间过程进行的，还是独立发育的。本研究的目的是探讨体外培养的多能干细胞的早期造血功能。通过利用小分子CHIR99021的贴壁培养无血清分化系统诱导人类多能干细胞向各种造血系分化，我们发现，与OP9共培养造血诱导系统相比，CHIR99021的应用改变了造血的早期步骤，如成血管细胞、血管生成造血祖细胞和造血内皮。重要的是，它与成血管细胞祖细胞的缺失、CD43(+)（原始造血标志物）表达的缺失以及在半固体培养基中形成红细胞集落的主要发育有关。这些数据支持了一个假设，即在人类多能干细胞分化过程中，原始和最终程序的分化先于成血管细胞阶段。此外，我们已经表明原始造血的抑制与造血潜能的增加有关，这是一个富有成效的发现，因为在翻译应用中对淋巴细胞和髓细胞的需求越来越大。(C) 2018iseh -血液学与干细胞学会。Elsevier Inc.出版。
Improving our understanding of the intricacies of hematopoietic specification of induced or embryonic human pluripotent stem cells is beneficial for many areas of research and translational medicine. Currently, it is not clear whether, during human pluripotent stem cells hematopoietic differentiation in vitro, the maturation of definitive progenitors proceeds through a primitive progenitor (hemangioblast) intermediate or if it develops independently. The objective of this study was to investigate the early stages of hematopoietic specification of pluripotent stem cells in vitro. By implementing an adherent culture, serum-free differentiation system that utilizes a small molecule, CHIR99021, to induce human pluripotent stem cells toward various hematopoietic lineages, we established that, compared with the OP9 coculture hematopoietic induction system, the application of CHIR99021 alters the early steps of hematopoiesis such as hemangioblasts, angiogenic hematopoietic progenitors, and hemogenic endothelium. Importantly, it is associated with the loss of hemangioblast progenitors, loss of CD43(+ )(primitive hematopoietic marker) expression, and predominant development of blastforming unit erythroid colonies in semisolid medium. These data support the hypothesis that the divergence of primitive and definitive programs during human pluripotent stem cells differentiation precedes the hemangioblast stage. Furthermore, we have shown that the inhibition of primitive hematopoiesis is associated with an increase in hematopoietic potential, which is a fruitful finding due to the growing need for lymphoid and myeloid cells in translational applications. (C) 2018 ISEH - Society for Hematology and Stem Cells. Published by Elsevier Inc.