Hematopoietic stem cells (HSCs) manifest impaired recovery and self-renewal with a concomitant increase in differentiation when exposed to ambient air as opposed to physioxia. Mechanism(s) behind this distinction are poorly understood but have the potential to improve stem cell transplantation. Single-cell RNA sequencing of HSCs in physioxia revealed upregulation of HSC self-renewal genes and downregulation of genes involved in inflammatory pathways and HSC differentiation. HSCs under physioxia also exhibited downregulation of the epigenetic modifier Tet2. Tet2 is α-ketoglutarate, iron- and oxygen-dependent dioxygenase that converts 5-methylcytosine to 5-hydroxymethylcytosine, thereby promoting active transcription. We evaluated whether loss of Tet2 affects the number and function of HSCs and hematopoietic progenitor cells (HPCs) under physioxia and ambient air. In contrast to wild-type HSCs (WT HSCs), a complete nonresponsiveness of Tet2-/- HSCs and HPCs to changes in oxygen tension was observed. Unlike WT HSCs, Tet2-/- HSCs and HPCs exhibited similar numbers and function in either physioxia or ambient air. The lack of response to changes in oxygen tension in Tet2-/- HSCs was associated with similar changes in self-renewal and quiescence genes among WT HSC-physioxia, Tet2-/- HSC-physioxia and Tet2-/- HSC-air. We define a novel molecular program involving Tet2 in regulating HSCs under physioxia.

中文翻译：

---

生理氧诱导的造血干细胞中 Tet2 的下调有助于增强自我更新。

当造血干细胞（HSC）暴露于环境空气而不是生理氧时，其恢复和自我更新能力受损，并伴随分化增加。这种区别背后的机制尚不清楚，但有潜力改善干细胞移植。生理氧状态下 HSC 的单细胞 RNA 测序揭示了 HSC 自我更新基因的上调以及参与炎症途径和 HSC 分化的基因的下调。生理氧下的 HSC 也表现出表观遗传修饰剂 Tet2 的下调。Tet2 是 α-酮戊二酸、铁和氧依赖性双加氧酶，可将 5-甲基胞嘧啶转化为 5-羟甲基胞嘧啶，从而促进活性转录。我们评估了 Tet2 的缺失是否会影响生理氧和环境空气下 HSC 和造血祖细胞 (HPC) 的数量和功能。与野生型 HSC (WT HSC) 相比，观察到 Tet2-/- HSC 和 HPC 对氧张力变化完全无反应。与 WT HSC 不同，Tet2-/- HSC 和 HPC 在生理氧或环境空气中表现出相似的数量和功能。Tet2-/- HSC 对氧张力变化缺乏反应与 WT HSC-physioxia、Tet2-/- HSC-physioxia 和 Tet2-/- HSC-air 中自我更新和静止基因的类似变化有关。我们定义了一种涉及 Tet2 在生理氧下调节 HSC 的新型分子程序。