Hematopoietic lineage skewing and intestinal epithelia degeneration in aged mice with telomerase RNA component deletion

Abstract

A deletion of telomerase RNA component (Terc−/−) in C57BL/6 (B6) mice resulted in hematopoietic lineage skewing with increased neutrophils and CD11b+ myeloid cells and decreased red blood cells and CD45R+ B lymphocytes when animals reach ages older than 12 months. There was no decline in bone marrow (BM) c-Kit+Sca-1+Lin− (KSL) cells in old Terc−/− mice, and the lineage skewing phenomenon was not transferred when BM cells from old Terc−/− donors were transplanted into young B6 recipients. Necropsy and histological examinations found minimal to no change in the lung, spleen and liver but detected severe epithelia degeneration, ulceration and infection in small and large intestines, leading to enteritis, typhlitis and colitis in old Terc−/− mice. In a mouse model of dextran-sulfate-sodium-induced typhlitis and colitis, development of intestinal pathology was associated with increases in neutrophils and CD11b+ myeloid cells and a decrease in CD45R+ B cells, similar to those observed in old Terc−/− mice. Treatment of 11–13 month old Terc−/− mice with antibiotic trimethoprim-sulfa water reduced neutrophils and myeloid cells and increased B lymphocytes in the blood, indicating that mitigation of intestinal infection and inflammation could alleviate hematological abnormalities in old Terc−/− animals.

The Telomerase Complex Directly Controls Hematopoietic Stem Cell Differentiation and Senescence in an Induced Pluripotent Stem Cell Model of Telomeropathy

“…A link between intestinal infection and inflammation with impaired telomerase activity has also been shown in these animals. In contrast to our findings in vitro , normalization of myeloid cell numbers in TERC -/- mice following antibiotic treatment had no effect on the HSC compartment, suggesting that the effect of loss of TERC on myelopoietic changes is indirect ( Chen et al, 2015 ).…”

“…Telomere complex impairment is one of the first explanations for bone-marrow failure in dyskeratosis congenita, but several groups have highlighted a possible role for bone marrow mesenchymal stem cells in disease pathology. Specifically, mesenchymal stem cells lacking TERC are unable to sufficiently support healthy hematopoiesis ( Balakumaran et al, 2015 ; Chen et al, 2015 ). Nevertheless the role of specific members of the telomerase complex in telomeropathy progression remains inconclusive.…”

“…TERC -/- mouse models exhibit an increased proportion of myeloid cells and impaired red blood cell and B-cell development in older animals ( Ju et al, 2007 ; Chen et al, 2015 ). A link between intestinal infection and inflammation with impaired telomerase activity has also been shown in these animals.…”

Telomere dysfunction impairs intestinal differentiation and predisposes to diet-induced colitis

“…Previous studies have shown that telomere shortening in the intestine predisposes to inflammation through pathways that are incompletely understood and mainly attributed to ISC compromise 33,45,46 . To determine the impact of telomere dysfunction on the intestinal epithelium (IE), we performed RNA-seq analysis on the IE from the proximal intestine of young WT and TKO mice.…”

“…The presence of immature enterocytes explains the observed barrier defect in mice and, potentially, in human patients with intestinal inflammation, in which a barrier defect has been suggested to drive intestinal inflammation 36,45,66 . This barrier defect predisposes to inflammation through a pathological interaction with the microbiome based on the significant amelioration of inflammation when the microbial load is reduced after a fructose-rich diet or in aged TKO mice 45,46 . The importance of the intestinal epithelium as a driver of intestinal inflammation is further strengthened by the finding that intestinal inflammation is reduced when telomerase is reactivated specifically in the intestinal epithelium 45 .…”