Increased molecular and functional heterogeneity of hematopoietic stem cells contributes to age-related decline of tissue and body function

Aging is a process accompanied by functional decline in tissues and organs with great social and medical consequences. Previous studies have demonstrated that aged hematopoietic stem cells (HSCs) are functionally compromised, which at least partly contributes to aging-related decline of the body health. However, the underlying mechanism is largely unknown. Here we reveal a clear heterogeneity of old HSCs, which can be marked by the CD150 levels. Comparative molecular and functional analyses revealed that CD150low HSCs from old mice have a younger aging clock, transcriptome, and better repopulation capacity compared to that of the CD150high HSCs. Mechanistically, CD150high HSCs from old mice have greatly compromised differentiation capacity compared to that of the CD150low HSCs. Importantly, decreasing the CD150high HSC ratio in old mice can alleviate aging-related functional decline. Thus, our study not only reveals how HSC heterogeneity contributes to aging, but also points to a potential way for rejuvenation. We have conducted RNA sequencing and single-cell RNA sequencing to invesitgate the transcriptomic heterogenetity in HSCs aging. RRBS profiling is conducted and applied to calculate the epigenetic age.