Limited rejuvenation of aged hematopoietic stem cells in young bone marrow niche

Hematopoietic stem cell (HSCs) exhibit functional alterations, such as reduced regenerative capacity and myeloid-biased differentiation, with age. HSC niche, which is essential for the maintenance of HSCs, also undergo considerable changes with aging. However, it has been technically difficult to directly evaluate the contribution of niche aging to HSC aging without niche-damaging myeloablation in HSC transplantation assays. Here, we transplanted an excess of aged HSCs into young mice without pre-conditioning. Although aged HSCs successfully engrafted in intact young BM niche, they poorly generated downstream progenitors and exhibited sustained myeloid-biased differentiation. Secondary transplantation revealed no significant recovery of aged HSCs in regenerative and differentiation capacity. Young niche largely restored the transcriptional profiles of aged HSCs, but scarcely did their DNA methylation profiles. These results indicate that the restoration of niche is not sufficient for the rejuvenation of aged HSCs, highlighting a key role for age-associated cell-intrinsic defects in HSC aging.