Cellular senescence in human liver under normal aging and cancer.

CDKN1A+ senescent cells were identified across multiple liver cell types including hepatocytes, fibroblasts, cholangiocytes, and endothelial cells.

• Senescent populations were characterized by CDKN1A expression across distinct cell types in the liver
• These populations were associated with age, liver disease, or cancer depending on cell type
• The study profiled 43 normal human livers spanning multiple ages and fibrosis stages
• Complementary platforms included single-cell multiome, Xenium spatial transcriptomics, and CODEX

Senescence programs differed between aged and fibrotic livers, with similar patterns recapitulated in fibrotic mouse models.

• Aged and fibrotic livers showed distinct senescence signatures despite both conditions exhibiting CDKN1A+ populations
• Fibrotic mouse models were used to validate and complement findings from human liver profiling
• The distinction between aging-associated and fibrosis-associated senescence suggests condition-specific mechanisms

CDKN1A+ senescent hepatocytes localized periportally in spatial analyses.

• Xenium spatial transcriptomics was used to determine the spatial organization of senescent hepatocytes
• Periportal localization of CDKN1A+ hepatocytes suggests a zonation-dependent senescence pattern
• Spatial organization was assessed across 43 normal human livers

SERPINE1+ aging-associated hepatocytes formed spatial clusters potentially mediated by Claudins and THBS1.

• SERPINE1 (also known as PAI-1) marked a distinct aging-associated hepatocyte population
• These cells formed spatial clusters detectable by Xenium spatial transcriptomics
• Claudins and THBS1 were identified as potential mediators of this spatial clustering

Fibrotic regions contained CXCL12+ senescent fibroblasts that interacted with CXCR4+ immune cells.

• CXCL12 expression marked senescent fibroblasts specifically in fibrotic regions of the liver
• CXCR4+ immune cells were identified as interaction partners of CXCL12+ fibroblasts
• This ligand-receptor interaction suggests a mechanism by which senescent fibroblasts recruit or communicate with immune cells in fibrotic liver

Chemotherapy intensified hepatocyte senescence by 5-fold relative to aging and induced unique CDKN2A+ populations.

• 24 colorectal cancer liver metastases were analyzed alongside normal liver samples
• Chemotherapy-associated senescence was 5-fold greater in hepatocytes compared to aging-associated senescence
• Chemotherapy uniquely induced CDKN2A+ senescent populations not prominently observed under aging or fibrosis conditions
• CDKN2A (encoding p16INK4a) expression distinguished chemotherapy-induced from other forms of senescence

Across all conditions, senescent cells shared activation of AP-1, pro-inflammatory cytokines, and apoptosis resistance.

• AP-1 transcription factor activation was a common feature of senescent cells regardless of the inducing condition
• Pro-inflammatory cytokine expression was shared across senescent cell populations, consistent with a senescence-associated secretory phenotype (SASP)
• Apoptosis resistance was identified as a shared characteristic across senescent cell populations
• These shared features were identified across aging, fibrosis, and cancer-associated senescence contexts
• The authors suggest these shared features represent 'therapeutic opportunities'

The study employed a multi-platform approach profiling 43 normal human livers across ages and fibrosis stages.

• Single-cell multiome (simultaneous RNA and ATAC sequencing) was used for transcriptomic and chromatin accessibility profiling
• Xenium spatial transcriptomics provided in situ spatial resolution of gene expression
• CODEX (co-detection by indexing) provided spatial protein-level data
• 24 colorectal cancer liver metastases were included to assess cancer-associated senescence
• Fibrotic mouse models provided additional validation of human findings