Frailty is an age-related syndrome that drives multiple physiological system impairments in some older adults, and its pathophysiological mechanisms remain unclear. We evaluated whether frailty-related biological processes could impair stem cell compartments, specifically the renal stem compartment, given that kidney dysfunctions are frequent in frailty. A well-characterized in vitro nephrosphere model of human adult renal stem/progenitor cells has been instrumental to and was appropriate for verifying this hypothesis in our current research. Evaluating the effects of plasma from older individuals with frailty (frail plasma) on allogeneic renal stem/progenitor cells, we showed significant functional impairment and nuclear DNA damage in the treated cells of the renal stem compartment. The analysis of the frail plasma revealed mitochondrial functional impairment associated with the activation of oxidative stress and a unique inflammatory mediator profile in frail individuals. In addition, the plasma of frail subjects also contained the highest percentage of DNA-damaged autologous circulating hematopoietic progenitor/stem cells. The integration of both molecular and functional data obtained allowed us to discern patterns associated with frailty status, irrespective of the comorbidities present in the frail individuals. The data obtained converged toward biological conditions that in frailty caused renal and hematopoietic impairment of stem cells, highlighting the possibility of concomitant exhaustion of several stem compartments.

中文翻译：

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衰弱综合征中肾脏和造血干细胞/祖细胞区室的损害：与氧化应激、血浆细胞因子谱和核 DNA 损伤有关


虚弱是一种与年龄相关的综合征，可导致一些老年人出现多种生理系统损伤，其病理生理机制尚不清楚。鉴于衰弱时经常出现肾功能障碍，我们评估了与衰弱相关的生物过程是否会损害干细胞区室，特别是肾干区室。在我们目前的研究中，人类成人肾干/祖细胞的特征明确的体外肾球模型有助于并适合验证这一假设。评估来自衰弱的老年人 （衰弱血浆） 的血浆对同种异体肾干/祖细胞的影响，我们显示肾干室的处理细胞中存在显着的功能损伤和核 DNA 损伤。对脆弱血浆的分析揭示了与氧化应激激活相关的线粒体功能障碍以及虚弱个体的独特炎症介质特征。此外，虚弱受试者的血浆中还含有最高比例的 DNA 损伤的自体循环造血祖细胞/干细胞。获得的分子和功能数据的整合使我们能够辨别与虚弱状态相关的模式，而不管虚弱个体中存在的合并症如何。获得的数据趋同于在虚弱中导致干细胞肾脏和造血功能损害的生物学条件，突出了几个干细胞区室同时耗竭的可能性。