A P21-Atd Mouse Model for Monitoring and Eliminating Senescent Cells and Its Application in Liver Regeneration Post Injury
MOLECULAR THERAPY（2024）
Tongji Univ
Abstract
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 fi cally study the undefined fi ned mechanism for p21-expressing senescent cells in the aged and liver injury animals. The successful expressions of these genes enabled in vitro fl ow cytometric sorting, in vivo 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 p21ATD mice and fumarylacetoacetate hydrolase (Fah)-/-- /- mice of liver injury, showed that the majority of their senescent hepatocytes were the phenotype of p21+ + rather than p16+. + . Furthermore, eliminating the p21-expressing hepatocytes significantly fi cantly promoted the engraftment of grafted hepatocytes and facilitated liver repopulation, resulting in significant fi cant 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.
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Key words
p21,cellular senescence,aging,liver regeneration,senescent cell elimination
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