Senescence-associated Transcriptomic Signatures and Spatial Localization of Immune Cells in Male and Female Mammalian Hearts

Norah Allam

Document Type

Article

Publication Date

2025

JAX Location

JMG

Abstract

Aging remodels the cardiac immune landscape and contributes to sex- and cell-specific risks for cardiovascular disease. In this study, we characterized transcriptomic profiles of macrophages and dendritic cells from young and aged male and female murine hearts, focusing on p21+ senescence-associated populations, using integrated single-cell, single-nucleus, and spatial transcriptomics. Male aged immune cells exhibited differential gene expression and pathways associated with inflammation, calcification, and maladaptive tissue remodeling, marked by enhanced pro-inflammatory and apoptotic pathways alongside suppression of contractile and metabolic functions. In contrast, female immune cells showed elevated insulin-like growth factor (IGF) signaling and TGF-β pathway activity, reflecting metabolic robustness and a balanced senescent state characterized by pro-survival and profibrotic signaling. Spatial analyses revealed sex- and cell-specific colocalizations supporting these divergent pathways, including male-enriched survival and Hippo pathway suppressive interactions and female-enriched IGF-axis signaling in valvular regions. In regards to senescence-associated profiling, p21+ senescent cells displayed stronger growth arrest and stress response signatures than general aged cells, with males favoring pathogenic calcification and inflammation, while females emphasized proteostasis and DNA damage responses. This integrated molecular and spatial characterization unveils fundamental sex/cell-specific and senescence-dependent differences in cardiac immune aging, offering new insights for therapeutic strategies against age-related cardiovascular diseases.

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