Abstract
Hypercholesterolemia accelerates the phenotypes of aging in hematopoietic stem cells (HSCs). As yet, little is known about the underlying mechanism. We found that hypercholesterolemia downregulates Ten eleven translocation 1 (Tet1) in HSCs. The total HSC population was increased, while the long-term (LT) population, side population and reconstitution capacity of HSCs were significantly decreased in Tet1−/− mice. Expression of the Tet1 catalytic domain in HSCs effectively restored the LT population and reconstitution capacity of HSCs isolated from Tet1−/− mice. While Tet1 deficiency upregulated the expression of p19 and p21 in HSCs by decreasing the H3K27me3 modification, the restoration of Tet1 activity reduced the expression of p19, p21 and p27 by restoring the H3K27me3 and H3K36me3 modifications on these genes. These results indicate that Tet1 plays a critical role in maintaining the quiescence and reconstitution capacity of HSCs and that hypercholesterolemia accelerates HSC aging phenotypes by decreasing Tet1 expression in HSCs.
Highlights
Adult tissue-specific stem cells maintain tissue homeostasis and regenerative potential
We found that the expression of ten-eleven translocation (Tet)[1] was significantly lower in hematopoietic stem cells (HSCs) (KTLS cells, defined as Sca1+cKit+Lin−CD90.1−/low) isolated from hypercholesterolemic mice than in that of wild type (WT) control mice (Fig. 1a)
We found that Ten eleven translocation 1 (Tet1)−/− KTLS cells contributed 56% of bone marrow reconstitution, while WT KTLS cells made the contribution around 50%
Summary
Adult tissue-specific stem cells maintain tissue homeostasis and regenerative potential. We found that the expression of Tet[1] was significantly lower in HSCs (KTLS cells, defined as Sca1+cKit+Lin−CD90.1−/low) isolated from hypercholesterolemic mice than in that of wild type (WT) control mice (Fig. 1a). PCR analysis showed that Tet[1] deficiency and hypercholesterolemia did not change the expression of HSC markers, including CD34, Sca-1 and cKit (Supplementary Fig. 2).
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