A NOTCH4 intron 28 regulatory element controls arterial specification and lymphoid development from hPSCs

Blood Vessels, Thrombosis & Hemostasis Pub Date : 2025-01-15 DOI:10.1016/j.bvth.2025.100046

Ho Sun Jung , Divine Mensah Sedzro , Peng Liu , Igor I. Slukvin

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Abstract

NOTCH signaling plays a critical role in arterial specification, and the formation of transient definitive lymphomyeloid progenitors and hematopoietic stem cells from hemogenic endothelium (HE). To investigate NOTCH signaling mechanisms critical for arterial and lymphoid specification, we performed single-cell multiomics analysis of human pluripotent stem cells (hPSCs) at different stages of hematopoietic differentiation. These studies uncovered the activation of NOTCH signaling and the arterial program, along with dynamic changes in related regulons throughout the HE specification and the endothelial-to-hematopoietic transition. We revealed that expression of NOTCH4 in the arterial endothelium is controlled by a cis-regulatory element within intron 28 (NOTCH4in28) through SOX17 binding. Deletion of NOTCH4in28 in conventional and conditional iSOX17 hPSCs impaired the formation of the early wave DLL4⁺CXCR4^+/− HE with arterial features, as well as hematopoietic progenitors with T and natural killer lymphoid potential. Collectively, we provide compelling evidence that NOTCH4 and the NOTCH4in28 cis-regulatory element play an important role in arterial specification and lymphoid development in hPSC cultures.

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NOTCH4内含子28调控元件控制来自hPSCs的动脉规范和淋巴细胞发育

摘要notch信号在动脉规范、瞬时终代淋巴祖细胞和造血干细胞的形成过程中起着至关重要的作用。为了研究NOTCH信号传导机制对动脉和淋巴细胞规范的关键作用，我们对处于造血分化不同阶段的人多能干细胞（hPSCs）进行了单细胞多组学分析。这些研究揭示了NOTCH信号和动脉程序的激活，以及HE规范和内皮到造血转变过程中相关调控的动态变化。我们发现NOTCH4在动脉内皮中的表达受内含子28 （NOTCH4in28）中的顺式调控元件通过SOX17结合控制。在常规和条件iSOX17 hPSCs中，NOTCH4in28的缺失会损害具有动脉特征的早期波DLL4+CXCR4+/−HE的形成，以及具有T和自然杀伤淋巴细胞潜能的造血祖细胞。总之，我们提供了令人信服的证据，证明NOTCH4和NOTCH4in28顺式调节元件在hPSC培养中动脉规范和淋巴细胞发育中起重要作用。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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Blood Vessels, Thrombosis & Hemostasis

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