Heterogeneity in hematopoietic stem cell enables adaptation to the aged microenvironment [scRNA-seq]

Using cellular barcoding and single cell-RNA-seq to longitudinally sample shared sister-clones across hetero- and homochronic transplants in mice, we quantify (i) intra- and inter-cellular transcriptional heterogeneity in young and old HSC, (ii) differential self-renewal and clonal fitness of HSC in reconstituted hematopoiesis, and (iii) clone-wise associations between pre-existing programs and fitness in aging contexts via predictive machine learning models.

Old HSC exhibit greater heterogeneity and rates of generation of heterogeneity, driven by specific gene sets with known roles in HSC fitness. Old HSC exhibit higher self-renewal in old relative to young hosts, likely reflecting adaptation over life to the aged altered niche. Clones with higher fitness in aged mice are enriched for signatures of quiescence, genome integrity/DNA repair, and inflammaging when compared to lower-fitness clones before transplantation.