Cui Xinyu, Dong Yu, Zhan Qiang, Huang Yixin, Zhu Qianshu, Zhang Zihao, Yang Guang, Wang Liping, Shen Shijun, Zhao Jia, Lin Zhiyi, Sun Jiatong, Su Zhongqu, Xiao Yihan, Zhang Chuyu, Liang Yuwei, Shen Lu, Ji Lichen, Zhang Xuguang, Yin Jiqing, Wang Hong, Chen Zhiyang, Ju Zhenyu, Jiang Cizhong, Le Rongrong, Gao Shaorong
Clinical and Translational Research Center of Shanghai First Maternity & Infant Hospital, Frontier Science Center for Stem Cells, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China.
Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Orthopaedic Department of Tongji Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China.
Sci China Life Sci. 2025 May;68(5):1209-1225. doi: 10.1007/s11427-024-2754-9. Epub 2024 Dec 27.
Inflammation is a driving force of hematopoietic stem cells (HSCs) aging, causing irreversible exhaustion of functional HSCs. However, the underlying mechanism of HSCs erosion by inflammatory insult remains poorly understood. Here, we find that transient LPS exposure primes aged HSCs to undergo accelerated differentiation at the expense of self-renewal, leading to depletion of HSCs. Meanwhile, the central regulator nuclear factor kappa B (NF-κB) mediating functional impairment by inflammation insult induces differential transcriptional response in aged HSCs compared with young HSCs, with precocious activation of myeloid lineage genes. Altered compartmentalization and chromatin loop formation are associated with aging-related differential transcriptional response in HSCs upon lipopolysaccharide (LPS) stimulation. Mechanistically, enhancer and promoter regions of myeloid lineage genes in aged HSCs are more accessible and display more rapid and prominent CTCF occupancy upon LPS stimulation. Our study provides comprehensive resources for the three-dimensional (3D) genome structure of HSCs and sheds light into the ordered genome organization and the associated transcriptome signature underlying HSCs aging.
炎症是造血干细胞（HSC）衰老的驱动力，会导致功能性HSC不可逆转的耗竭。然而，炎症损伤侵蚀HSC的潜在机制仍知之甚少。在此，我们发现短暂暴露于脂多糖（LPS）会促使衰老的HSC以自我更新为代价加速分化，导致HSC耗竭。同时，介导炎症损伤功能障碍的核心调节因子核因子κB（NF-κB）在衰老的HSC中诱导了与年轻HSC不同的转录反应，髓系谱系基因过早激活。脂多糖（LPS）刺激后，HSC中改变的区室化和染色质环形成与衰老相关的差异转录反应有关。机制上，衰老HSC中髓系谱系基因的增强子和启动子区域更容易接近，并且在LPS刺激后显示出更快速和显著的CTCF占据。我们的研究为HSC的三维（3D）基因组结构提供了全面的资源，并揭示了HSC衰老背后有序的基因组组织和相关的转录组特征。
