Age-Related Alterations in Human Hematopoietic Stem and Progenitor Cells

Aging of the human hematopoietic system is typically associated with various disease states and functional changes, such as decreased bone marrow (BM) cellularity, reduced adaptive immune responses and increased incidence of anemia. Similar observations are made in mice and have been shown to, at least in part, have their origin already at the hematopoietic stem cell (HSC) level. Current ideas on age-related alterations of the hematopoietic system are to a large extent based on studies of the murine system, as studies on the human system are few and to some extent contradictory. We further detailed human hematopoietic aging by comparing adult BM samples from young and old individuals, as well as samples obtained from cord blood (CB). We observed similar changes to those observed in mice, including a functional decline in the proliferative and cloning potential of HSCs and impaired lymphoid cell production with age. We revealed alterations in the frequencies of immunophenotypically defined HSCs and progenitor cells of the megakaryocytic/erythroid, granulocyte/macrophage and lymphoid lineages within the CD34+ population, consistent with the observed HSC impairment and decreased lymphopoiesis. Transcriptome profiling demonstrated a myelo-meg-erythroid bias and downregulation of genes associated with lymphoid specification in the adult aged HSC compartment compared to the young. Further, single cell gene expression analysis of 45 individual genes, including lineage affiliated genes and a panel of transcription factors, in a large number of HSCs isolated from young and old BM and CB revealed heterogeneity within the HSC compartment as well as a pattern of transcription fluctuation for a set of genes across age boundaries. Collectively, we demonstrate age-related alterations in the human hematopoietic system to have, in least in part, their origin already in the immature HSC level and find a number of genes differentially expressed within the HSCs compartment and with age.