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Tytuł:
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Hematopoiesis under telomere attrition at the single-cell resolution.
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Autorzy:
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Thongon, Natthakan
Ma, Feiyang
Santoni, Andrea
Marchesini, Matteo
Fiorini, Elena
Rose, Ashley
Adema, Vera
Ganan-Gomez, Irene
Groarke, Emma M.
Gutierrez-Rodrigues, Fernanda
Chen, Shuaitong
Lockyer, Pamela
Schneider, Sarah
Bueso-Ramos, Carlos
Montalban-Bravo, Guillermo
Class, Caleb A.
Soltysiak, Kelly A.
Pellegrini, Matteo
Sahin, Ergun
Bertuch, Alison A.
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Temat:
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TELOMERES
HEMATOPOIESIS
HEMATOPOIETIC stem cells
HUMAN stem cells
BIOTRANSFORMATION (Metabolism)
WNT signal transduction
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Źródło:
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Nature Communications; 11/25/2021, Vol. 12 Issue 1, p1-13, 13p
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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. .This is not the summary of the paper [ABSTRACT FROM AUTHOR]
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