Wisconsin National Primate Research Center, University of Wisconsin Graduate School, 1220 Capitol Court, Madison, WI 53715, USA.
Departments of Statistics and of Biostatistics and Medical Informatics, Carbone Cancer Center, University of Wisconsin-Madison, Madison, WI, USA.
Cell Rep. 2021 Feb 16;34(7):108758. doi: 10.1016/j.celrep.2021.108758.
SOX17 has been implicated in arterial specification and the maintenance of hematopoietic stem cells (HSCs) in the murine embryo. However, knowledge about molecular pathways and stage-specific effects of SOX17 in humans remains limited. Here, using SOX17-knockout and SOX17-inducible human pluripotent stem cells (hPSCs), paired with molecular profiling studies, we reveal that SOX17 is a master regulator of HOXA and arterial programs in hemogenic endothelium (HE) and is required for the specification of HE with robust lympho-myeloid potential and DLL4CXCR4 phenotype resembling arterial HE at the sites of HSC emergence. Along with the activation of NOTCH signaling, SOX17 directly activates CDX2 expression, leading to the upregulation of the HOXA cluster genes. Since deficiencies in HOXA and NOTCH signaling contribute to the impaired in vivo engraftment of hPSC-derived hematopoietic cells, the identification of SOX17 as a key regulator linking arterial and HOXA programs in HE may help to program HSC fate from hPSCs.
SOX17 已被牵涉到动脉的特化以及在鼠胚胎中造血干细胞（HSCs）的维持。然而，关于 SOX17 在人类中的分子途径和阶段特异性影响的知识仍然有限。在这里，我们使用 SOX17 敲除和 SOX17 诱导的人类多能干细胞（hPSCs），结合分子谱研究，揭示了 SOX17 是造血内皮（HE）中 HOXA 和动脉程序的主调控因子，并且对于具有强大的淋巴髓样潜力和 DLL4CXCR4 表型的 HE 的特化是必需的，这种表型类似于 HSC 出现部位的动脉 HE。随着 NOTCH 信号的激活，SOX17 直接激活 CDX2 的表达，导致 HOXA 簇基因的上调。由于 HOXA 和 NOTCH 信号的缺陷导致 hPSC 衍生的造血细胞在体内植入能力受损，因此将 SOX17 鉴定为连接 HE 中的动脉和 HOXA 程序的关键调控因子，可能有助于从 hPSCs 中编程 HSC 命运。
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