1007 – GENOMIC REPETITIVE ELEMENTS SIGNAL SURFACE B2M TO BLOCK PHAGOCYTOSIS OF HSCS

IF 2.5 4区 医学 Q2 HEMATOLOGY
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引用次数: 0

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 Tlr3 signaling regulated b2m expression. Targeting b2m or Tlr3 reduced the HSC clonality. Elevated B2m levels correlated with high expression of repetitive elements (RE) transcripts. Overall, our data suggest that RE-associated dsRNA could interact with TLR3 to stimulate surface expression of B2m on HSPCs. These findings suggest that the balance of Calr and B2m regulates macrophage-HSC interactions and defines hematopoietic clonality.

1007 - 基因组重复元件向表面 B2M 发出信号,阻止 HSC 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,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相关的dsRNA可与TLR3相互作用,刺激HSPC表面B2m的表达。这些研究结果表明,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。
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来源期刊
Experimental hematology
Experimental hematology 医学-血液学
CiteScore
5.30
自引率
0.00%
发文量
84
审稿时长
58 days
期刊介绍: Experimental Hematology publishes new findings, methodologies, reviews and perspectives in all areas of hematology and immune cell formation on a monthly basis that may include Special Issues on particular topics of current interest. The overall goal is to report new insights into how normal blood cells are produced, how their production is normally regulated, mechanisms that contribute to hematological diseases and new approaches to their treatment. Specific topics may include relevant developmental and aging processes, stem cell biology, analyses of intrinsic and extrinsic regulatory mechanisms, in vitro behavior of primary cells, clonal tracking, molecular and omics analyses, metabolism, epigenetics, bioengineering approaches, studies in model organisms, novel clinical observations, transplantation biology and new therapeutic avenues.
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