Transcripts of repetitive DNA elements signal to block phagocytosis of hematopoietic stem cells

IF 44.7 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES Science Pub Date : 2024-09-13 DOI:10.1126/science.adn1629

Cecilia Pessoa Rodrigues, Joseph M. Collins, Song Yang, Catherine Martinez, Ji Wook Kim, Chhiring Lama, Anna S. Nam, Clemens Alt, Charles Lin, Leonard I. Zon

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Abstract

Macrophages maintain hematopoietic stem cell (HSC) quality by assessing cell surface Calreticulin (Calr), an “eat-me” signal induced by reactive oxygen species (ROS). Using zebrafish genetics, we identified Beta-2-microglobulin (B2m) as a crucial “don’t eat-me” signal on blood stem cells. A chemical screen revealed inducers of surface Calr that promoted HSC proliferation without triggering ROS or macrophage clearance. Whole-genome CRISPR-Cas9 screening showed that Toll-like receptor 3 (Tlr3) signaling regulated b2m expression. Targeting b2m or tlr3 reduced the HSC clonality. Elevated B2m levels correlated with high expression of repetitive element (RE) transcripts. Overall, our data suggest that RE-associated double-stranded RNA could interact with TLR3 to stimulate surface expression of B2m on hematopoietic stem and progenitor cells. These findings suggest that the balance of Calr and B2m regulates macrophage-HSC interactions and defines hematopoietic clonality.

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重复 DNA 元素的转录本发出信号，阻止造血干细胞的吞噬作用

巨噬细胞通过评估细胞表面的Calreticulin（Calr）来维持造血干细胞（HSC）的质量，Calr是活性氧（ROS）诱导的 "吃我 "信号。通过斑马鱼遗传学研究，我们发现β-2-微球蛋白（B2m）是造血干细胞上一个重要的 "不吃我 "信号。化学筛选发现，表面Calr的诱导剂能促进造血干细胞增殖，而不会引发ROS或巨噬细胞清除。全基因组CRISPR-Cas9筛选显示，Toll样受体3（Tlr3）信号调节b2m的表达。靶向b2m或Tlr3可降低造血干细胞的克隆性。B2m水平的升高与重复元素（RE）转录本的高表达相关。总之，我们的数据表明，RE相关双链RNA可与TLR3相互作用，刺激造血干细胞和祖细胞表面B2m的表达。这些发现表明，Calr和B2m的平衡调节着巨噬细胞-造血干细胞的相互作用，并决定着造血克隆性。

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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来源期刊

Science 综合性期刊-综合性期刊

CiteScore

61.10

自引率

0.90%

发文量

审稿时长

2.1 months

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