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

作者：Cecília Pessoa Rodrigues, Joseph M. Collins, Song Yang, Catherine Martinez, Ji Wook Kim, Chhiring Lama, Anna S. Nam, Clemens Alt, Charles P. Lin, Leonard I. Zon · 发表于：Science · 年份：2024 · DOI：10.1126/science.adn1629 · 被引用次数：19 · 研究领域：Zebrafish Biomedical Research Applications、Immune Cell Function and Interaction、Immune cells in cancer

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.