A Cellular and Transcriptomic Atlas of the Aged Mouse Hematopoietic System

Aging is a dominant risk factor for chronic diseases characterized by the functional decline of tissues and organs. During aging, the hematopoietic system declines in regenerative capacity – seemingly attributable to increases in DNA damage, replicative stress, and autophagic flux – resulting in skewing towards a myeloid lineage and away from a lymphoid lineage. Here, we characterized the transcriptomic and cellular landscape of the aged C57Bl6/J mouse hematopoietic system using a combination of bulk RNAseq and single cell RNAseq (scRNAseq). We show that aging leads to global transcriptional alterations in bulk peripheral blood mononuclear cells (PBMCs), lineage marker-depleted bone marrow cells (lin- BM), and in hematopoietic stem cells (HSCs) marked by lineage- (lin-) Sca1+cKit+ (LSK+). These changes indicate widespread activation of inflammatory processes, namely in PBMCs and lin-BM cells. Interestingly, there is also a downregulation of cell cycle genes in HSCs during aging. scRNAseq across 39 hematopoietic cell types revealed age-related skewing in cell composition. Aged PBMCs showed significant decreases in CD4 and CD8 naïve cells concomitant with increases in CD4/8 memory and CD8 exhausted T cell populations. Lin- BM cells showed significant myeloid skewing in common myeloid progenitor (CMP) cells as well as in the HSC population. We also identified a unique HSC population marked by increased Vwf, Wwtr1, and Clca3a1 expression that does not exist in young HSCs, thus likely marking true aged HSCs. Collectively, this works encompasses a significant resource for uses in therapeutically targeting the aged hematopoietic system.