2024年9月13日，美国哈佛大学
通过斑马鱼遗传学研究，研究人员发现β-2-微球蛋白（B2m）是血液干细胞上的关键“别吞噬我”信号。化学筛选揭示了能够诱导表面钙网蛋白（Calr）的化合物，这些化合物促进了造血干细胞（HSC）增殖，但不会触发活性氧（ROS）或巨噬细胞清除。
全基因组CRISPR-Cas9筛选显示，Toll样受体3（Tlr3）信号通路调控b2m的表达。靶向b2m或tlr3会降低HSC的克隆性。B2m水平升高与重复元件（RE）转录本的高表达相关。
总体而言，这些数据显示，RE相关的双链RNA可能与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的平衡调节了巨噬细胞与HSC的相互作用，并决定了造血克隆性。
研究人员表示，巨噬细胞通过检测细胞表面的Calr维持HSC的质量，钙网蛋白是一种由ROS诱导的“吞噬我”信号。
附：英文原文
Title: Transcripts of repetitive DNA elements signal to block phagocytosis of hematopoietic stem cells
Author: 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
Issue&Volume: 2024-09-13
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.
DOI: adn1629
Source: https://www.science.org/doi/10.1126/science.adn1629