Chronic inflammation or ageing result in a functional reduction in Hematopoietic Stem And Progenitor Cells (HSPC). Numerous autoimmune, inflammatory, and hematologic cancers are linked to haploinsufficiency of A20, or TNFAIP3, an innate immune regulator. We found that the expression of A20 is much lower in elderly HSPC as compared to youthful HSPC, which is based on a prior analysis of the epigenomic and transcriptome changes that occur throughout normal human ageing. Here, we demonstrate how the partial reduction of A20 expression in young HSPC leads to aging-related characteristics. Particularly, myeloid-biased hematopoiesis, lower HSPC fitness, and enlargement of the HSPC pool were all effects of heterozygous deletion of A20 in hematopoietic cells. These findings imply that altered A20 expression in HSPC contributes to an aging-like phenotype and that inflammatory conditions and ageing may share an underlying mechanism for reduced HSPC function.
