Dynamic stem cell selection safeguards the genomic integrity of the epidermis- Kato et al

Maintaining genomic integrity and stability is crucial for life, yet no tissue-driven mechanism that robustly safeguards the epithelial genome has been discovered. Epidermal stem cells (EpiSCs) continuously replenish the stratified layers of keratinocytes that protect organisms against various environmental stresses. To study the dynamics of DNA-damaged cells in tissues, we devised an in vivo fate tracing system for EpiSCs with DNA double-strand breaks (DSBs) and demonstrate that those cells exit from their niche. The clearance of EpiSCs with DSBs is caused by selective differentiation and delamination through the DNA damage response (DDR)-p53-Notch axis with the downregulation of ITGB1. Moreover, concomitant enhancement of symmetric cell divisions of surrounding stem cells indicates that the selective elimination of cells with DSBs is coupled with the augmented clonal expansion of intact stem cells. These data collectively demonstrate that the dynamic coupling of cell-autonomous and non-cell-autonomous mechanisms coordinately maintains the genomic quality of the epidermis.

维持基因组完整性与稳定性对生命活动至关重要，但目前尚未发现能够稳定保护上皮基因组的组织驱动机制。表皮干细胞（Epidermal stem cells, EpiSCs）可持续更新复层角质形成细胞，从而为机体抵御各类环境胁迫提供保护。为研究组织中DNA损伤细胞的动态变化，我们构建了携带DNA双链断裂（DNA double-strand breaks, DSBs）的表皮干细胞体内命运示踪系统，并证实此类细胞会脱离其所在的微环境。携带DNA双链断裂的表皮干细胞的清除，是通过DNA损伤应答（DNA damage response, DDR）-p53-Notch信号轴介导的选择性分化与分层脱落实现的，该过程伴随整合素β1（ITGB1）的表达下调。此外，周围干细胞的对称细胞分裂增强这一现象表明，DNA损伤细胞的选择性清除，与未受损干细胞的克隆扩增增强相耦联。综上，本研究数据证实，细胞自主与非细胞自主机制的动态协同耦联，可共同维持表皮组织的基因组质量。