Spatial and single-cell profiling of the metabolome, transcriptome and epigenome of the aging mouse liver
Chrysa Nikopoulou, Niklas Kleinenkuhnen, Swati Parekh, Tonantzi Sandoval, Christoph Ziegenhain, Farina Schneider, Patrick Giavalisco, Kat-Folz Donahue, Anna Juliane Vesting, Marcel Kirchner, Mihaela Bozukova, Christian Vossen, Janine Altmüller, Thomas Wunderlich, Rickard Sandberg, Vangelis Kondylis, Achim Tresch, Peter Tessarz
Abstract
Tissues within an organism and even cell types within a tissue can age with different velocities. However, it is unclear whether cells of one type experience different aging trajectories within a tissue depending on their spatial location. Here, we used spatial transcriptomics in combination with single-cell ATAC-seq and RNA-seq, lipidomics and functional assays to address how cells in the male murine liver are affected by age-related changes in the microenvironment. Integration of the datasets revealed zonation-specific and age-related changes in metabolic states, the epigenome and transcriptome. The epigenome changed in a zonation-dependent manner and functionally, periportal hepatocytes were characterized by decreased mitochondrial fitness, whereas pericentral hepatocytes accumulated large lipid droplets. Together, we provide evidence that changing microenvironments within a tissue exert strong influences on their resident cells that can shape epigenetic, metabolic and phenotypic outputs.