Cellular senescence in human liver under normal aging and cancer.

Alla Karpova, Xiang Li, Chien-Wei Peng, Kelsey L Gallant, Daniel R Rapp, Daniel M Alligood, Andrew J Houston, Alex Park, Andre Luiz N Targino da Costa, Wen-Hung Chou, Michael D Iglesia, John M Herndon, Kathleen Byrnes, Nataly Naser Al Deen, Preet Lal, Xiangwei Fang, Reyka G Jayasinghe, Jeffrey A Blatnik, William G Hawkins, Dominic E Sanford, J Chris Eagon, Natasha Leigh, Maria Bernadette M Doyle, L Michael Brunt, William C Chapman, Roheena Z Panni, Darren R Cullinan, Sherri R Davies, Jun Guo, Matthew A Wyczalkowski, Michael C Wendl, Hong Zhang, Colin A Martin, Brad W Warner, Milan G Chheda, Sheila A Stewart, Feng Chen, Ryan C Fields, Li Ding

Department of Medicine, Washington University in St. Louis, St. Louis, MO 63110, USA; McDonnell Genome Institute, Washington University in St. Louis, St. Louis, MO 63108, USA.Department of Medicine, Washington University in St. Louis, St. Louis, MO 63110, USA; McDonnell Genome Institute, Washington University in St. Louis, St. Louis, MO 63108, USA. · pubmed

Paper

Abstract

Cellular senescence, a stress-induced program causing stable cell-cycle arrest, is a hallmark of liver aging, fibrosis, and cancer. However, the cell-type-specific mechanisms, spatial organization, and cancer-associated alterations in the liver remain unclear. We profiled 43 normal human livers spanning ages and fibrosis stages using a single-cell multiome, Xenium spatial transcriptomics, and CODEX, complemented by fibrotic mouse models and 24 colorectal cancer liver metastases. We found CDKN1A+ senescent hepatocytes, fibroblasts, cholangiocytes, and endothelial cells associated with age, liver disease, or cancer. Senescence differed between aged and fibrotic livers, with similar patterns in mice. Spatially, CDKN1A+ hepatocytes localized periportally, while SERPINE1+ aging-associated hepatocytes formed spatial clusters, potentially mediated by Claudins and THBS1. Fibrotic regions contained CXCL12+ senescent fibroblasts interacting with CXCR4+ immune cells. Chemotherapy intensified senescence in hepatocytes by 5-fold relative to aging and led to unique CDKN2A+ populations. Across conditions, senescent cells shared AP-1 activation, pro-inflammatory cytokines, and apoptosis resistance, suggesting therapeutic opportunities.

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Research summary

The paper claims that cellular senescence in various liver cell types is associated with aging and cancer, revealing distinct spatial and mechanistic patterns. This research is relevant as it explores the underlying mechanisms of cellular senescence, which is a key factor in aging and age-related diseases, potentially leading to therapeutic strategies that address the root causes of these conditions.

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