Hematopoiesis under telomere attrition at the single-cell resolution.
Natthakan ThongonFeiyang MaAndrea SantoniMatteo MarchesiniElena FioriniAshley RoseVera AdemaIrene Gañán-GómezEmma M GroarkeFernanda Gutierrez-RodriguesShuaitong ChenPamela LockyerSarah M SchneiderCarlos Bueso-RamosGuillermo Montalban-BravoCaleb A ClassKelly A SoltysiakMatteo PellegriniErgun SahinAlison A BertuchCourtney D D DiNardoGuillermo Garcia ManeroNeal S YoungKaren DwyerSimona CollaPublished in: Nature communications (2021)
The molecular mechanisms that drive hematopoietic stem cell functional decline under conditions of telomere shortening are not completely understood. In light of recent advances in single-cell technologies, we sought to redefine the transcriptional and epigenetic landscape of mouse and human hematopoietic stem cells under telomere attrition, as induced by pathogenic germline variants in telomerase complex genes. Here, we show that telomere attrition maintains hematopoietic stem cells under persistent metabolic activation and differentiation towards the megakaryocytic lineage through the cell-intrinsic upregulation of the innate immune signaling response, which directly compromises hematopoietic stem cells' self-renewal capabilities and eventually leads to their exhaustion. Mechanistically, we demonstrate that targeting members of the Ifi20x/IFI16 family of cytosolic DNA sensors using the oligodeoxynucleotide A151, which comprises four repeats of the TTAGGG motif of the telomeric DNA, overcomes interferon signaling activation in telomere-dysfunctional hematopoietic stem cells and these cells' skewed differentiation towards the megakaryocytic lineage. This study challenges the historical hypothesis that telomere attrition limits the proliferative potential of hematopoietic stem cells by inducing apoptosis, autophagy, or senescence, and suggests that targeting IFI16 signaling axis might prevent hematopoietic stem cell functional decline in conditions affecting telomere maintenance.
Keyphrases
- stem cells
- single cell
- hematopoietic stem cell
- bone marrow
- rna seq
- cell therapy
- endothelial cells
- high throughput
- cell cycle arrest
- oxidative stress
- single molecule
- cell death
- endoplasmic reticulum stress
- innate immune
- induced apoptosis
- cell free
- signaling pathway
- cell proliferation
- dendritic cells
- dna methylation
- genome wide
- mesenchymal stem cells
- dna repair
- transcription factor
- cancer therapy
- pluripotent stem cells
- low cost