A COMPREHENSIVE AGING SIGNATURE OF MURINE HEMATOPOIETIC STEM CELLS

Abstract

Blood cell production is detrimentally affected by age. This is manifested by impairment of immune response (immunosenescence) and development of a range of clinical conditions such as autoimmunity, anemia, and hematological malignancies. Many of these conditions are consequences of molecular age-related changes in hematopoietic stem cells (HSCs). Multiple studies have been published which document age-related transcriptional changes in murine HSCs. In an attempt to establish a definitive HSC aging signature we scanned PubMed and found 14 different studies that report gene expression changes in highly purified HSCs isolated from young and aged C57BL/6 mice. Out of these studies, we focused on 10 datasets that contained deposited raw expression data. By reanalyzing and comparing differently expressed (DE) genes of each of these different studies we observed striking heterogeneity; Irrespective of this massive study-to-study variability, we were able to identify 179 transcripts that were found to differentially expressed in at least 4 out of the 10 studies. Interestingly, the large majority of these DE genes were upregulated during aging. This collection of 179 HSC aging genes comprises the most comprehensive HSC aging signature to date. Unexpectedly, gene orthology analysis revealed that the HSC aging signature consists of largely of transcripts encoding for membrane associated proteins, receptors, and cell matrix and cytoskeleton proteins. This might suggest that HSC aging is associated with perturbed cross-talk between HSCs and their immediate microenvironment. The HSC aging signature can be used as a reference for future studies in order to determine the extent of molecular similarity of different genetic models and physiological aging.