Hematopoietic Stem Cell Senescence

描述（由申请人提供）：衰老小鼠的造血干细胞（HSC）优先失去再生适应性免疫系统的能力。这种向骨髓细胞和其他HSC异常产生的倾斜可能导致人类的免疫衰老。也就是说，在老年人中，疫苗接种反应的质量可能很差或不适当。引起这些变化的环境和潜在的机制在很大程度上是未知的。虽然化疗、放疗、DNA修复缺陷、端粒酶丧失和细胞因子升高会损害HSC，但在这些情况下，淋巴细胞潜能的选择性丧失尚未见报道。相比之下，我们发现反复暴露于极低剂量脂多糖的小鼠恢复的HSC中存在髓系扭曲、自我更新缺陷和其他与年龄相关的变化。尽管这些动物总体上健康状况良好，HSC的数量也正常。这些显著的发现表明，持续的低级别感染和相关的病原体产物可能导致HSC衰老并最终损害免疫力。类似的HSC变化可能是由与组织损伤和肥胖相关的内源性Toll样受体（TLR）配体引起的。我们现在将确定这种现象是否发生在其他TLR配体和炎症性肠病（IBD）动物模型中。此外，我们还将探讨损害造血干细胞的途径。这些发现有望为正常衰老以及许多慢性疾病（如艾滋病毒/艾滋病）提供信息，这些慢性疾病可能会加速免疫衰老。此外，可以发现一些造血恶性肿瘤的模式与年龄相关的变化的基础。

DESCRIPTION (provided by applicant): Hematopoietic stem cells (HSC) in aging mice preferentially lose the ability to regenerate the adaptive immune system. This skewing towards production of myeloid cells and other HSC abnormalities may contribute to the immunosenescence seen in humans. That is, the quality of responses to vaccination can be poor or inappropriate in aged individuals. The circumstances that elicit these changes and the underlying mechanisms are largely unknown. While HSC are harmed by chemotherapy, radiation, DNA repair defects, loss of telomerase and elevated cytokines, selective loss of lymphopoietic potential has not been reported in those circumstances. In contrast, we have found myeloid skewing, defective self-renewal and other age-related changes in HSC recovered from mice repeatedly exposed to very low doses of lipopolysaccharide. This is despite the fact that the animals were in generally good health and numbers of HSC were normal. These remarkable findings suggest that persistent low-grade infections and associated pathogen products might cause HSC senescence and ultimately compromise immunity. It is possible that similar HSC changes are caused by endogenous Toll- like receptor (TLR) ligands associated with tissue damage and obesity. We will now determine if the phenomenon occurs with other TLR ligands and in an animal model of inflammatory bowel disease (IBD). Additionally, we will explore the means through which HSC are harmed. The findings are expected to be informative about normal aging as well as many chronic conditions such as HIV/AIDS that may accelerate immunosenescence. Also, a basis may be found for age-related shifts in patterns of some hematopoietic malignancies. PUBLIC HEALTH RELEVANCE: Our immune systems become less effective in old age, and there is new evidence to suggest this can result from a history of low-grade infections. More study could reveal how to block or even reverse these consequences of aging.