Hand in hand: intrinsic and extrinsic drivers of aging and clonal hematopoiesis.
Hand in hand: intrinsic and extrinsic drivers of aging and clonal hematopoiesis.
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DOI：
10.1016/j.exphem.2020.09.197
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发表时间：
2020-11
影响因子：
2.6
通讯作者：
Trowbridge JJ
中科院分区：
文献类型：
--
作者：
SanMiguel JM;Young K;Trowbridge JJ
在过去的 25 年里，造血干细胞 (HSC) 老化在整个造血和免疫系统健康寿命中的重要性已得到认识。为了了解衰老过程中造血干细胞中发生的内在失调，人们在模型生物体中做了很多工作，目的是确定代表众所周知的“青春之泉”的可修改机制。最近，体细胞突变的发现为 HSC 提供了选择性优势，并在衰老过程中在造血系统中积累，称为克隆造血 (CH)，这激发了我们在这些体细胞突变的背景下重新审视许多先前定义的 HSC 衰老驱动因素。为了真正了解这些过程并全面了解 HSC 衰老的情况，正在进行和未来的研究必须包括调查 HSC 生态位或骨髓微环境随衰老发生的关键变化，因为越来越多的证据支持这些 HSC 外在改变提供了必要的炎症、信号通路激活或抑制以及其他有利于 HSC 衰老相关表型和 CH 的选择性压力。在这里，我们根据我们自己的实验室过去 8 年对这些机制的研究提出了我们的观点，并绘制了一条综合研究的路径，我们认为，这将为发现 HSC 和延长造血健康寿命的干预措施提供一个理想的机会。该路径包括研究不同个体中与衰老相关的 HSC 内在和 HSC 外在变化何时以及如何随时间累积，并开发新模型来跟踪和测试相关的 HSC 外在变化，以补充最近开发的创新 HSC 谱系追踪系统。
Over the past 25 years, the importance of hematopoietic stem cell (HSC) aging in overall hematopoietic and immune system healthspan has been appreciated. Much work has been done in model organisms to understand intrinsic dysregulation that occurs in HSCs during aging, with the goal of identifying modifiable mechanisms that represent the proverbial “fountain of youth”. Much more recently, the discovery of somatic mutations that are found to provide a selective advantage to HSCs and accumulate in the hematopoietic system during aging, termed clonal hematopoiesis (CH), inspires revisiting many of these previously defined drivers of HSC aging in the context of these somatic mutations. To truly understand these processes and develop a holistic picture of HSC aging, ongoing and future studies must include investigation of the critical changes that occur in the HSC niche or bone marrow microenvironment with aging, as increasing evidence supports that these HSC-extrinsic alterations provide necessary inflammation, signaling pathway activation or repression, and other selective pressures to favor HSC aging-associated phenotypes and CH. Here, we provide our perspectives based on the past 8 years of our own laboratory’s investigations into these mechanisms and chart a path for integrative studies that, in our opinion, will provide an ideal opportunity to discover HSC and hematopoietic healthspan-extending interventions. This path includes examining when and how aging-associated HSC-intrinsic and HSC-extrinsic changes accumulate over time in different individuals and developing new models to track and test relevant HSC-extrinsic changes, complementary to innovative HSC lineage tracing systems that have recently been developed.
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