Hematopoiesis Under Telomere Attrition at the Single-Cell Resolution

Authors

Natthakan Thongon
Feiyang Ma
Andrea Santoni
Matteo Marchesini
Elena Fiorini
Ashley Rose
Vera Adema
Irene Ganan-Gomez
Emma M Groarke
Fernanda Gutierrez-Rodrigues
Shuaitong Chen
Pamela Lockyer
Sarah Schneider
Carlos Bueso-Ramos
Guillermo Montalban-Bravo
Caleb A Class
Kelly A Soltysiak
Matteo Pellegrini
Ergun Sahin
Alison A Bertuch
Courtney D DiNardo
Guillermo Garcia-Manero
Neal S Young
Karen Dwyer
Simona Colla

Publication Date

11-25-2021

DOI

https://doi.org/10.1038/s41467-021-27206-7

PMID

34824242

PMCID

PMC8617077

PubMedCentral® Posted Date

11-25-2021

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

Animals, Bone Marrow Failure Disorders, Cell Self Renewal, Cellular Reprogramming, Hematopoiesis, Hematopoietic Stem Cells, Humans, Interferons, Megakaryocytes, Mice, Nuclear Proteins, Oligodeoxyribonucleotides, Phosphoproteins, Signal Transduction, Single-Cell Analysis, Telomere, Telomere Shortening

Abstract

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.

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