Blood stem cell aging and biomarker studies

 描述（申请人提供）：关于系统性衰老的机制，已经提出了多种理论，遗传、行为和环境因素都可能涉及其中。过去十年积累的证据发现，从成年到老年，干细胞活性出现可测量且连续的年龄依赖性下降，从而影响自然衰老过程中的组织稳态。识别指示干细胞衰老的生物标志物并了解衰老干细胞在功能上变得与年轻干细胞相似的机制对于监测衰老和设计针对与衰老相关的组织稳态和组织再生失衡的治疗方法非常重要。造血干细胞 (HSC) 在个体的一生中持续提供成熟的血细胞，这一过程称为造血。老年人免疫反应逐渐减弱、骨髓恶性肿瘤和贫血发病率增加被认为与 HSC 衰老有关。 HSC 衰老的分子机制仍不清楚，这阻碍了识别有用生物标志物、减缓或逆转 HSC 功能随年龄下降以及改善衰老后生活质量的合理方法。识别造血衰老的有效生物标志物将有助于诊断和治疗与年龄相关的血液状况和疾病。我们实验室发表的研究表明，在小鼠模型中，HSC 在衰老时会失去极性，这种现象与干细胞内在的细胞内酶 Cdc42 和典型 Wnt3A 到非典型 Wnt5A 信号开关的年龄依赖性升高有关。我们的数据进一步表明，Wnt5a-Cdc42 信号轴的遗传和药理学靶向可以在功能上使衰老的 HSC 恢复活力。有趣的是，已发表的全基因组关联研究发现外周血细胞中的Cdc42表达与人类的发病率和死亡率密切相关，我们的初步数据表明衰老时人类HSC的非极性以及外周血细胞中的Cdc42活性与献血者年龄之间呈正相关，这意味着Cdc42可能是造血衰老的有效生物标志物和/或有效靶点。在目前的研究中，我们提出了综合实验和观察策略，利用最先进的小鼠模型，寻找 HSC 中的新型信号开关 Wnt5A-Cdc42 与单个干细胞水平上 HSC 衰老表型的因果关系，包括骨髓-淋巴谱系失衡以及与衰老相关的干细胞自我更新和植入减少。我们将进一步研究针对 Cdc42 信号轴（衰老过程中 HSC 极性调节的关键）的潜力，以恢复几种 HSC 衰老表型的潜力。我们的研究将在动物模型中建立血液干细胞衰老的新机制，该机制可以转化为人类衰老，并且可能在其他干细胞系统和组织/器官再生中具有价值。

 DESCRIPTION (provided by applicant): A number of theories have been proposed regarding the mechanisms of systemic aging, and genetic, behavioral and environmental factors may all be involved. Evidence accumulated over the past decade has found measurable and successive age-dependent decline in stem cell activity from adulthood to old age to affect tissue homeostasis during natural aging. Identifying biomarkers indicative of stem cell aging and understanding mechanisms under which aged stem cells become functionally similar to young stem cells are important for monitoring aging and devising treatments for aging-associated imbalance in tissue homeostasis and tissue regeneration. Hematopoietic stem cells (HSCs) continuously provide mature blood cells during the lifespan of individuals in a process termed hematopoiesis. A progressive reduction in the immune response in the elderly and an increased incidence of myeloid malignancy, as well as anemia is thought to be linked to HSC aging. Molecular mechanism of HSC aging remain unclear, hindering rational approaches to identify useful biomarkers and to slow or reverse the decline of HSC function with age and to improve the quality of life upon aging. Identifying valid biomarkers of aging in hematopoiesis will assist n diagnosis and treatments for age- related blood conditions and diseases. Published work from our labs indicates that in mouse models, HSCs lose polarity upon aging, a phenomenon associated with stem cell intrinsic age-dependent elevation of an intracellular enzyme, Cdc42, and a canonical Wnt3A to non-canonical Wnt5A signaling switch. Our data further demonstrates that genetic and pharmacologic targeting of this Wnt5a-Cdc42 signaling axis functionally rejuvenates aged HSCs. Interestingly, published genome-wide association studies have found that Cdc42 expression in peripheral blood cells is closely linked to morbidity and mortality in humans, and our preliminary data demonstrate apolarity in human HSCs upon aging and a positive correlation between Cdc42 activity in peripheral blood cells and age of the blood donor, implying that Cdc42 might be a valid biomarker and/or valid target of aging in hematopoiesis. In the present studies, we propose integrated experimental and observational strategies to seek a causal relationship of our novel signaling switch in HSCs, Wnt5A-Cdc42, with aging phenotypes of HSCs at the single stem cell level, including myeloid-lymphoid lineage imbalances and the aged associated reduction of stem cell self-renewal and engraftment, using state-of-the-art mouse models. We will further examine the potential of targeting the Cdc42 signaling axis, key for HSC polarity regulation in aging, for rejuvenation of several HSC aging phenotypes. Our studies will establish a new mechanism of blood stem cell aging in animal models that could be translated to human aging, and may have values in other stem cell systems and tissue/organ regeneration.