{"title":"1007 – GENOMIC REPETITIVE ELEMENTS SIGNAL SURFACE B2M TO BLOCK PHAGOCYTOSIS OF HSCS","authors":"Leonard Zon","doi":"10.1016/j.exphem.2024.104308","DOIUrl":null,"url":null,"abstract":"<div><p>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.</p></div>","PeriodicalId":12202,"journal":{"name":"Experimental hematology","volume":"137 ","pages":"Article 104308"},"PeriodicalIF":2.5000,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0301472X2400167X/pdfft?md5=ad31a74465a3bc77dbf5c3126c919cd7&pid=1-s2.0-S0301472X2400167X-main.pdf","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Experimental hematology","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0301472X2400167X","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"HEMATOLOGY","Score":null,"Total":0}
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.
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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