Cellular senescence associates with pathological aging and tissue dysfunctions. Studies utilizing mouse models for cell lineage tracings have emphasized the importance of senescence heterogeneity in different organs and cell types. Here, we constructed a p21- (Akaluc - tdTomato - Diphtheria Toxin Receptor [DTR]) (ATD) mouse model to specifically study the undefined mechanism for p21-expressing senescent cells in the aged and liver injury animals. The successful expressions of these genes enabled flow cytometric sorting, tracing, and elimination of p21-expressing senescent cells. During the natural aging process, p21-expressing cells were found in various tissues of p21-ATD mice. Eliminating p21-expressing cells in the aged p21-ATD mice recovered their multiple biological functions. p21-ATD/Fah mice, bred from p21-ATD mice and fumarylacetoacetate hydrolase (Fah) mice of liver injury, showed that the majority of their senescent hepatocytes were the phenotype of rather than . Furthermore, eliminating the p21-expressing hepatocytes significantly promoted the engraftment of grafted hepatocytes and facilitated liver repopulation, resulting in significant recovery from liver injury. Our p21-ATD mouse model serves as an optimal model for studying the pattern and function of p21-expressing senescent cells under the physical and pathological conditions during aging.

中文翻译：

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监测和消除衰老细胞的p21-ATD小鼠模型及其在损伤后肝再生中的应用

细胞衰老与病理性衰老和组织功能障碍有关。利用小鼠模型进行细胞谱系追踪的研究强调了不同器官和细胞类型中衰老异质性的重要性。在这里，我们构建了 p21-（Akaluc - tdTomato - 白喉毒素受体 [DTR]）（ATD）小鼠模型，专门研究老年和肝损伤动物中表达 p21 的衰老细胞的未定义机制。这些基因的成功表达使得流式细胞仪能够对表达 p21 的衰老细胞进行分选、追踪和消除。在自然衰老过程中，在 p21-ATD 小鼠的各种组织中发现了表达 p21 的细胞。消除老年 p21-ATD 小鼠中表达 p21 的细胞后，它们恢复了多种生物学功能。 p21-ATD/Fah 小鼠由 p21-ATD 小鼠和肝损伤的富马酰乙酰乙酸水解酶 (Fah) 小鼠交配而成，显示其大多数衰老肝细胞为 而非 的表型。此外，消除表达p21的肝细胞可显着促进移植肝细胞的植入并促进肝脏再生，从而使肝损伤显着恢复。我们的 p21-ATD 小鼠模型是研究衰老过程中物理和病理条件下表达 p21 的衰老细胞的模式和功能的最佳模型。