Transcripts of repetitive DNA elements signal to block phagocytosis of hematopoietic stem cells-Reference-Cited by-同舟云学术

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

Published:2024-09-13 Issue:6714 Volume:385 Page:
ISSN:0036-8075
Container-title:Science
language:en
Short-container-title:Science

Author:

Pessoa Rodrigues Cecilia¹²^ORCID,Collins Joseph M.¹²^ORCID,Yang Song¹^ORCID,Martinez Catherine²^ORCID,Kim Ji Wook¹²^ORCID,Lama Chhiring³,Nam Anna S.³^ORCID,Alt Clemens⁴,Lin Charles⁴⁵^ORCID,Zon Leonard I.¹²^ORCID

Affiliation:

1. Howard Hughes Medical Institute, Boston Children’s Hospital Boston, MA, USA.

2. Harvard Stem Cell Institute, Stem Cell and Regenerative Biology Department, Harvard University, Cambridge, MA, USA.

3. Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA.

4. Wellman Center for Photomedicine, Mass General Research Institute, Boston, MA, USA.

5. Center for Systems Biology, Massachusetts General Hospital, Boston, MA, USA.

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.

Publisher

American Association for the Advancement of Science (AAAS)

Link

https://www.science.org/doi/pdf/10.1126/science.adn1629

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