Yanai Hagai, McNeely Taylor, Ayyar Saipriya, Leone Michael, Zong Le, Park Bongsoo, Beerman Isabel
Epigenetics and Stem Cell Unit, Translational Gerontology Branch, National Institute On Aging, NIH, 251 Bayview Blvd, Suite 100/10C220, Baltimore, MD, 21224, USA.
Geroscience. 2025 Apr;47(2):1873-1886. doi: 10.1007/s11357-024-01360-4. Epub 2024 Oct 11.
Aging of hematopoietic stem cells (HSCs) is implicated in various aging phenotypes, including immune dysfunction, anemia, and malignancies. The role of HSC proliferation in driving these aging phenotypes, particularly under stress conditions, remains unclear. Therefore, we induced forced replications of HSCs in vivo by a cyclical treatment with low-dose fluorouracil (5FU) and examined the impact on HSC aging. Our findings show that proliferative stress induces several aging phenotypes, including altered leukocyte counts, decreased lymphoid progenitors, accumulation of HSCs with high expression of Slamf1, and reduced reconstitution potential, without affecting stem cell self-renewal capacity. The divisional history of HSCs was imprinted in the DNA methylome, consistent with functional decline. Specifically, DNA methylation changes included global hypermethylation in non-coding regions and similar frequencies of hypo- and hyper-methylation at promoter regions, particularly affecting genes targeted by the PRC2 complex. Importantly, initial forced replication promoted DNA damage repair accumulated with age, but continuous proliferative stress led to the accumulation of double-strand breaks, independent of functional decline. Overall, our results suggest that HSC proliferation can drive some aging phenotypes primarily through epigenetic mechanisms, including DNA methylation changes.
造血干细胞（HSC）的衰老与多种衰老表型有关，包括免疫功能障碍、贫血和恶性肿瘤。HSC增殖在驱动这些衰老表型中的作用，尤其是在应激条件下，仍不清楚。因此，我们通过低剂量氟尿嘧啶（5FU）的周期性治疗在体内诱导HSC的强制复制，并研究其对HSC衰老的影响。我们的研究结果表明，增殖应激会诱导多种衰老表型，包括白细胞计数改变、淋巴祖细胞减少、高表达Slamf1的HSC积累以及重建潜力降低，而不影响干细胞的自我更新能力。HSC的分裂历史印记在DNA甲基化组中，与功能衰退一致。具体而言，DNA甲基化变化包括非编码区的整体高甲基化以及启动子区低甲基化和高甲基化的相似频率，尤其影响PRC2复合体靶向的基因。重要的是，最初的强制复制促进了随年龄积累的DNA损伤修复，但持续的增殖应激导致双链断裂的积累，这与功能衰退无关。总体而言，我们的结果表明，HSC增殖主要通过表观遗传机制，包括DNA甲基化变化，来驱动一些衰老表型。
