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低氧诱导的造血干细胞中 Tet2 的下调有助于增强自我更新。

Physioxia-induced downregulation of Tet2 in hematopoietic stem cells contributes to enhanced self-renewal.

机构信息

Department of Microbiology and Immunology.

Department of Medical and Molecular Genetics, and.

出版信息

Blood. 2022 Sep 15;140(11):1263-1277. doi: 10.1182/blood.2022015499.

DOI:10.1182/blood.2022015499
PMID:35772013
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9479026/
Abstract

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.

摘要

造血干细胞（HSCs）在暴露于大气环境中时，与低氧相比，其自我更新和恢复能力受损，同时分化增加。导致这种差异的机制尚不清楚，但有可能改善干细胞移植。低氧环境下 HSCs 的单细胞 RNA 测序显示，HSC 自我更新基因上调，参与炎症途径和 HSC 分化的基因下调。低氧环境下的 HSCs 还表现出表观遗传修饰因子 Tet2 的下调。Tet2 是一种 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，从而促进活跃转录。我们评估了 Tet2 的缺失是否会影响低氧和大气环境下 HSCs 和造血祖细胞（HPCs）的数量和功能。与野生型 HSCs（WT HSCs）相比，Tet2-/- HSCs 和 HPCs 对氧张力变化完全无反应。与 WT HSCs 不同，Tet2-/- HSCs 和 HPCs 在低氧或大气环境中表现出相似的数量和功能。Tet2-/- HSCs 对氧张力变化无反应与 WT HSC-低氧、Tet2-/- HSC-低氧和 Tet2-/- HSC-空气之间的自我更新和静止基因的相似变化有关。我们定义了一个涉及 Tet2 的新分子程序，用于调节低氧环境下的 HSCs。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7f02/9479026/b148aacf1696/bloodBLD2022015499f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7f02/9479026/fd895ca08ccd/bloodBLD2022015499absf1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7f02/9479026/bd0b6354d75c/bloodBLD2022015499f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7f02/9479026/1b3b63a9cf80/bloodBLD2022015499f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7f02/9479026/29e5cd800566/bloodBLD2022015499f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7f02/9479026/2be00dcd9448/bloodBLD2022015499f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7f02/9479026/e085a171fe4b/bloodBLD2022015499f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7f02/9479026/b148aacf1696/bloodBLD2022015499f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7f02/9479026/fd895ca08ccd/bloodBLD2022015499absf1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7f02/9479026/bd0b6354d75c/bloodBLD2022015499f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7f02/9479026/1b3b63a9cf80/bloodBLD2022015499f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7f02/9479026/29e5cd800566/bloodBLD2022015499f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7f02/9479026/2be00dcd9448/bloodBLD2022015499f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7f02/9479026/e085a171fe4b/bloodBLD2022015499f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7f02/9479026/b148aacf1696/bloodBLD2022015499f6.jpg

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