Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Orthopedic Department of Tongji Hospital, School of Medicine, Tongji University, Shanghai, 200065, China.
Department of Urology, Tongji Hospital, Tongji University School of Medicine, Shanghai, 200065, China.
Nat Commun. 2024 Jun 8;15(1):4904. doi: 10.1038/s41467-024-49318-6.
Age-related depletion of stem cells causes tissue degeneration and failure to tissue regeneration, driving aging at the organismal level. Previously we reported a cell-non-autonomous DAF-16/FOXO activity in antagonizing the age-related loss of germline stem/progenitor cells (GSPCs) in C. elegans, indicating that regulation of stem cell aging occurs at the organ system level. Here we discover the molecular effector that links the cell-non-autonomous DAF-16/FOXO activity to GSPC maintenance over time by performing a tissue-specific DAF-16/FOXO transcriptome analysis. Our data show that dos-3, which encodes a non-canonical Notch ligand, is a direct transcriptional target of DAF-16/FOXO and mediates the effect of the cell-non-autonomous DAF-16/FOXO activity on GSPC maintenance through activating Notch signaling in the germ line. Importantly, expression of a human homologous protein can functionally substitute for DOS-3 in this scenario. As Notch signaling controls the specification of many tissue stem cells, similar mechanisms may exist in other aging stem cell systems.
年龄相关的干细胞耗竭导致组织退化和组织再生失败，从而导致机体水平的衰老。先前我们报道了在秀丽隐杆线虫中，一种非细胞自主的 DAF-16/FOXO 活性拮抗生殖干细胞/祖细胞（GSPCs）的年龄相关丢失，表明干细胞衰老的调节发生在器官系统水平。在这里，我们通过进行组织特异性 DAF-16/FOXO 转录组分析，发现了将非细胞自主的 DAF-16/FOXO 活性与 GSPC 维持联系起来的分子效应子。我们的数据表明，dos-3 编码一种非典型的 Notch 配体，是 DAF-16/FOXO 的直接转录靶标，并通过在生殖系中激活 Notch 信号转导，介导非细胞自主的 DAF-16/FOXO 活性对 GSPC 维持的影响。重要的是，人同源蛋白的表达可以在这种情况下替代 DOS-3 发挥功能。由于 Notch 信号转导控制着许多组织干细胞的特化，类似的机制可能存在于其他衰老的干细胞系统中。
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