Researchers developed novel genetic tools to trace, ablate, and manipulate p16^Ink4a+^ senescent cells, revealing their distinct roles in liver fibrosis and repair. Senescent macrophages promote fibrosis, while endothelial cells aid in tissue recovery.
By Vijay Kumar MalesuReviewed by Susha Cheriyedath, M.Sc.Oct 7 2024 New genetic tools reveal the dual roles of senescent cells in liver disease—macrophages drive fibrosis, while endothelial cells repair damage, unlocking potential for targeted therapies.
Background Cellular senescence is crucial in processes like aging, cancer, and disease. Induced by stress, it involves cell-cycle arrest, cyclin-dependent kinase inhibitors, and a senescence-associated secretory phenotype . Senescent cells have both harmful roles, such as promoting aging and disease, and beneficial ones, like tumor suppression and tissue repair.
Nonalcoholic steatohepatitis was induced using a choline-deficient L-amino acid diet for 12 weeks, with only male mice utilized to prevent gender-related variation. For small interfering Ribonucleic Acid transfection, cells were transfected with siRNA using Lipofectamine RNA interference MAX reagent, followed by incubation in a complete medium containing FBS before harvesting for analysis.
Fluorescence imaging of various organs from aging p16-tdT mice revealed an increase in tdT+ cells with age, particularly in neurons of the cerebral cortex and endocrine cells in the pancreas. These tdT+ cells showed strong senescence-associated phenotypes, such as elevated SASP factors and reduced proliferative capacity, confirming the diverse senescent cell populations in aged tissues.
In addition, a new genetic tool called Sn-cTracer was developed for the ablation of p16Ink4a+ cells. Ablation of p16Ink4a+ macrophages in liver fibrosis significantly reduced fibrosis, whereas eliminating p16Ink4a+ ECs exacerbated liver injury. This differential outcome demonstrated that senescent macrophages promote fibrosis, while senescent ECs play a reparative role.
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