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.

随着机体衰老，造血干细胞（hematopoietic stem cell, HSC）的内在活性逐渐下降，进而引发组织稳态受损、移植后造血植入能力降低以及疾病易感性升高。然而，衰老是否同样会作用于造血干细胞龛（HSC niche），削弱其支持HSC功能的能力，目前仍未明确。本研究通过体内长期标记滞留实验证实，老年标记滞留（labelling retaining, LR）造血干细胞是老年小鼠体内静息程度最高的HSC亚群，同时具备最强的再生能力与细胞极性，且这类细胞主要定植于窦周龛（perisinusoidal niche）内。此外，本研究证实，血窦龛（sinusoidal niche）与窦周Nes-GFP低表达细胞（Nes-GFPlow cells）在衰老过程中，其形态、结构与数量均得到了独特的保留。最后，本研究发现清髓性化疗（myeloablative chemotherapy）可选择性破坏老年小鼠的血窦龛，这一现象与老年小鼠的造血功能衰竭及存活率下降密切相关。综上，本研究首次系统阐明了衰老状态下造血干细胞龛的功能改变，并揭示窦周龛可通过独特的保留机制，保护HSC免受衰老的负面影响。