Age-related changes in the hematopoietic compartment are primarily attributed to cell-intrinsic alterations in hematopoietic stem cells (HSCs); however, the contribution of the aged microenvironment has not been adequately evaluated. Understanding the role of the bone marrow (BM) microenvironment in supporting HSC function may prove to be beneficial in treating age-related functional hematopoietic decline. Here, we determined that aging of endothelial cells (ECs), a critical component of the BM microenvironment, was sufficient to drive hematopoietic aging phenotypes in young HSCs. We used an ex vivo hematopoietic stem and progenitor cell/EC (HSPC/EC) coculture system as well as in vivo EC infusions following myelosuppressive injury in mice to demonstrate that aged ECs impair the repopulating activity of young HSCs and impart a myeloid bias. Conversely, young ECs restored the repopulating capacity of aged HSCs but were unable to reverse the intrinsic myeloid bias. Infusion of young, HSC-supportive BM ECs enhanced hematopoietic recovery following myelosuppressive injury and restored endogenous HSC function in aged mice. Coinfusion of young ECs augmented aged HSC engraftment and enhanced overall survival in lethally irradiated mice by mitigating damage to the BM vascular microenvironment. These data lay the groundwork for the exploration of EC therapies that can serve as adjuvant modalities to enhance HSC engraftment and accelerate hematopoietic recovery in the elderly population following myelosuppressive regimens.

中文翻译：

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内皮移植可恢复衰老的造血干细胞功能

造血区室中与年龄相关的变化主要归因于造血干细胞（HSC）中的细胞内在变化。但是，尚未充分评估老化的微环境的贡献。了解骨髓（BM）微环境在支持HSC功能中的作用可能证明对治疗年龄相关的功能性造血功能下降是有益的。在这里，我们确定了内皮细胞（EC）的老化是BM微环境的关键组成部分，足以驱动年轻HSC中的造血老化表型。我们使用了离体造血干细胞和祖细胞/ EC（HSPC / EC）共培养系统，以及小鼠骨髓抑制性损伤后的体内EC输注，以证明老年EC损害了年轻HSC的繁殖活性并赋予了髓样偏见。相反，年轻的EC恢复了老年HSC的繁殖能力，但无法逆转内在的髓样偏见。输注年轻的，支持HSC的BM ECs增强了骨髓抑制性损伤后的造血功能恢复，并恢复了年老小鼠的内源性HSC功能。通过减少对BM血管微环境的损害，年轻EC的共注入增加了致死剂量照射小鼠的HSC植入年龄，并提高了整体存活率。这些数据为探索EC治疗奠定了基础，这些EC治疗可作为佐剂治疗方法，以增强骨髓抑制治疗后老年人中HSC的植入并加速造血功能的恢复。HSC支持的BM ECs增强了骨髓抑制性损伤后的造血功能恢复，并恢复了年老小鼠的内源性HSC功能。通过减少对BM血管微环境的损害，年轻EC的共注入增加了致死剂量照射小鼠的HSC植入年龄，并提高了整体存活率。这些数据为探索EC治疗奠定了基础，这些EC治疗可作为佐剂治疗方法，以增强骨髓抑制治疗后老年人中HSC的植入并加速造血功能的恢复。HSC支持的BM ECs增强了骨髓抑制性损伤后的造血功能恢复，并恢复了年老小鼠的内源性HSC功能。通过减少对BM血管微环境的损害，年轻EC的共注入增加了致死剂量照射小鼠的HSC植入年龄，并提高了整体存活率。这些数据为探索EC治疗奠定了基础，这些EC治疗可作为佐剂治疗方法，以增强骨髓抑制治疗后老年人中HSC的植入并加速造血功能的恢复。