Hypoxia-inducible factor (HIF-1α), a core transcription factor responding to changes in cellular oxygen levels, is closely associated with a wide range of physiological and pathological conditions. However, its differential impacts on vascular cells types and molecular programs modulating human vascular homeostasis and regeneration remain largely elusive. Here, we applied CRISPR/Cas9-mediated gene editing of human embryonic stem cells (hESCs) and directed differentiation to generate HIF-1α-deficient human vascular cells including vascular endothelial cells (VECs), vascular smooth muscle cells (VSMCs), and mesenchymal stem cells (MSCs), as a platform for discovering cell type-specific hypoxia-induced response mechanisms. Through comparative molecular profiling across cell types under normoxic and hypoxic conditions, we provide insight into the indispensable role of HIF-1α in the promotion of ischemic vascular regeneration. We found human MSCs to be the vascular cell type most susceptible to HIF-1α deficiency, and that transcriptional inactivation of ANKZF1, an effector of HIF-1α, impaired pro-angiogenic processes. Altogether, our findings deepen the understanding of HIF-1α in human angiogenesis and support further explorations of novel therapeutic strategies of vascular regeneration against ischemic damage.

中文翻译：

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人 ESC 衍生的血管细胞以 HIF-1α 依赖性方式促进血管再生。

缺氧诱导因子 (HIF-1α) 是一种响应细胞氧水平变化的核心转录因子，与多种生理和病理状况密切相关。然而，它对血管细胞类型和调节人类血管稳态和再生的分子程序的不同影响在很大程度上仍然难以捉摸。在这里，我们应用 CRISPR/Cas9 介导的人类胚胎干细胞 (hESC) 基因编辑并定向分化以产生 HIF-1α 缺陷型人类血管细胞，包括血管内皮细胞 (VEC)、血管平滑肌细胞 (VSMC) 和间充质细胞干细胞 (MSC)，作为发现细胞类型特异性缺氧诱导反应机制的平台。通过在含氧量正常和缺氧条件下对细胞类型进行比较分子分析，我们深入了解 HIF-1α 在促进缺血性血管再生中不可或缺的作用。我们发现人类 MSC 是最容易受到 HIF-1α 缺陷影响的血管细胞类型，并且 ANKZF1（HIF-1α 的效应子）的转录失活会损害促血管生成过程。总而言之，我们的研究结果加深了对 HIF-1α 在人类血管生成中的理解，并支持进一步探索针对缺血性损伤的血管再生新治疗策略。