Transcripts of repetitive DNA elements signal to block phagocytosis of hematopoietic stem cells.
Cecilia Pessoa RodriguesJoseph M CollinsSong P YangCatherine MartinezJi Wook KimChhiring LamaAnna S NamClemens AltCharles P LinLeonard I ZonPublished in: Science (New York, N.Y.) (2024)
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.
Keyphrases
- toll like receptor
- reactive oxygen species
- inflammatory response
- poor prognosis
- nuclear factor
- stem cells
- immune response
- crispr cas
- binding protein
- cell surface
- high frequency
- hematopoietic stem cell
- adipose tissue
- cell death
- induced apoptosis
- dna damage
- genome editing
- signaling pathway
- long non coding rna
- oxidative stress
- cell proliferation
- single molecule
- cancer therapy
- electronic health record
- endoplasmic reticulum stress
- nucleic acid