Quiescent hematopoietic stem cells with short telomeres accumulate genomic damage but are blocked from hematopoietic activation by senescence and apoptosis

Telomere shortening limits proliferative capacity of human cells and age dependent shortening of telomeres occurs in somatic tissues including hematopoietic stem cells (HSCs). It is currently unknown whether genomic and molecular damages occur in HSC induced by telomere shortening are transmitted to the progenitor cells. Here we show that telomere shortening results in DNA damage accumulation and gene expression changes in quiescent HSCs of aged mice. Upon activation, a subset of HSCs with elevated levels of DNA damage and p16 expression is blocked from cell cycle entry and apoptosis is induced in HSCs entering cell cycle. Activation of both checkpoints associates with normalization of DNA damage and gene expression profiles at early progenitor stages. These findings indicate that quiescent HSCs have an elevated tolerance to accumulate genomic alterations in response to telomere shortening but the transmission of these aberrations to the progenitor cell level is prevented by senescence and apoptosis.