Hematopoietic stem cells in perisinusoidal niches are protected from ageing [aged, GFP-label retaining HSCs]

With ageing, intrinsic hematopoietic stem cell (HSC) activity decreases, resulting in impaired tissue homeostasis, reduced engraftment following transplantation and increased susceptibility to diseases. However, whether ageing affects also the HSC niche impairing the capacity to support HSC function is still largely unknown. Here, by using in-vivo long-term label retention assays we demonstrate that aged labelling retaining (LR) HSCs, which are in the old mice the most quiescent HSC subpopulation with the highest regenerative capacity and cellular polarity, reside predominantly in perisinusoidal niches. Furthermore, we demonstrate that sinusoidal niches and perisinusoidal Nes-GFPlow cells are uniquely preserved in shape, morphology and number upon ageing. Finally, we show that myeloablative chemotherapy can selectively disrupt aged sinusoidal niches, which is linked to hematopoietic failure and decreased survival of aged mice. Overall, our data characterize for the first time the functional alterations of the aged HSC niche and unveil that perisinusoidal niches are uniquely preserved and protect HSCs from ageing. Single-cell RNA-Seq dataset of aged, GFP-label retaining HSCs. 37 aLR-HSCs and 28 anLR-HSCs were isolated in 4 biological repeats (total of 65 cells). All libraries were manually prepared using Illumina’s Nextera XT DNA Library preparation kit.