Wisconsin National Primate Research Center, University of Wisconsin, Madison, WI, 53715, USA.
Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, 53792, USA.
Nat Commun. 2018 May 8;9(1):1828. doi: 10.1038/s41467-018-04134-7.
NOTCH signaling is required for the arterial specification and formation of hematopoietic stem cells (HSCs) and lympho-myeloid progenitors in the embryonic aorta-gonad-mesonephros region and extraembryonic vasculature from a distinct lineage of vascular endothelial cells with hemogenic potential. However, the role of NOTCH signaling in hemogenic endothelium (HE) specification from human pluripotent stem cell (hPSC) has not been studied. Here, using a chemically defined hPSC differentiation system combined with the use of DLL1-Fc and DAPT to manipulate NOTCH, we discover that NOTCH activation in hPSC-derived immature HE progenitors leads to formation of CD144CD43CD73DLL4Runx1 + 23-GFP arterial-type HE, which requires NOTCH signaling to undergo endothelial-to-hematopoietic transition and produce definitive lympho-myeloid and erythroid cells. These findings demonstrate that NOTCH-mediated arterialization of HE is an essential prerequisite for establishing definitive lympho-myeloid program and suggest that exploring molecular pathways that lead to arterial specification may aid in vitro approaches to enhance definitive hematopoiesis from hPSCs.
NOTCH 信号通路对于胚胎主动脉-性腺-中肾区和胚胎外脉管系统中动脉的特化以及造血干细胞（HSCs）和淋巴-髓系祖细胞的形成是必需的，其来自具有造血潜能的血管内皮细胞的特定谱系。然而，NOTCH 信号通路在人多能干细胞（hPSC）中的造血内皮（HE）特化中的作用尚未被研究。在这里，我们使用化学定义的 hPSC 分化系统，结合 DLL1-Fc 和 DAPT 的使用来操纵 NOTCH，发现 NOTCH 在 hPSC 来源的未成熟 HE 祖细胞中的激活导致 CD144CD43CD73DLL4Runx1 + 23-GFP 动脉型 HE 的形成，其需要 NOTCH 信号通路来经历内皮细胞向造血细胞的转变，并产生明确的淋巴-髓系和红细胞。这些发现表明，HE 的 NOTCH 介导的动脉化是建立明确的淋巴-髓系程序的必要前提，并表明探索导致动脉特化的分子途径可能有助于体外方法增强 hPSC 中的确定性造血。
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