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The senescence-associated cell surfaceome reveals potential senotherapeutic targets in human and mouse cells

ABSTRACT: Excessive accumulation of senescent cells contributes to a wide range of physiological declines and age-related pathologies. Senotherapy targeting senescent cell surface molecules represents an attractive approach to eliminate senescent cells with high specificity and accessibility. However, the comprehensive identification of surface proteins specific to cellular senescence is lacking. Here, we conducted quantitative mass spectrometry analysis on enriched cell surface proteins across eight experimental models of senescence induced by genotoxic, oxidative or proteasome stress in both fetal- and adult-derived murine and human cell types. Our analyses revealed pronounced changes in expression profiles of surfaceome during senescence, as well as universal alterations in functional features of cell mechanics and extracellular matrix remodeling. The cell type- and inducer-specific senescence signatures were also carried out by in-depth comparative analysis of surface proteomic profiling in cells undergoing distinct senescence conditions. Our investigation elucidated the heterogeneity of senescence, which is preferentially determined by respective cell type, from the perspective of the surfaceome. Moreover, we identified four cell surface proteins with extracellular epitopes, which were selectively expressed in senescent cells but not in proliferating cells, and elevated in various tissues of old mice and in the brain of an Alzheimer's disease mouse model. Our findings expand current understanding of senescence phenotypes that contribute to the intricate interactions between senescence cells and their extracellular milieu. The identified senescence surface biomarkers hold the potential to selectively capture and eliminate different senescent cell populations and subpopulations in the context of aging and age-related diseases in vivo.

ORGANISM(S): Homo Sapiens (human) Mus Musculus (mouse)

SUBMITTER: Dr. Dan Ehninger

PROVIDER: PXD048921 | JPOST Repository | Sun Jan 26 00:00:00 GMT 2025

REPOSITORIES: jPOST

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			Action	DRS
	Dec202021_HUVEC_Ctrl_1_TL_LFQ_95min_120K_8-15K_cycle2_dec-tr.raw	Raw
	Dec202021_HUVEC_Ctrl_2_TL_LFQ_95min_120K_8-15K_cycle2_dec-tr.raw	Raw
	Dec202021_HUVEC_Ctrl_3_TL_LFQ_95min_120K_8-15K_cycle2_dec-tr.raw	Raw
	Dec202021_HUVEC_H2o2_1_TL_LFQ_95min_120K_8-15K_cycle2_dec-tr.raw	Raw
	Dec202021_HUVEC_H2o2_2_TL_LFQ_95min_120K_8-15K_cycle2_dec-tr.raw	Raw

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Project description:The presence of senescent cells in the aging/degenerating human disc is now well-recognized. Senescent cells are viable, cannot divide, remain metabolically active and accumulate within the disc over time. Molecular analysis of senescent cells in tissue, however, offers a special challenge since there are no cell surface markers for senescence which would let one use fluorescence-activated cell sorting as a method for separating out senescent cells. Here we use a novel experimental design using laser capture microdissection to selectively separately harvest senescent and non-senescent annulus cells in paraffin-embedded tissue, and then compare their gene expression with microarray analysis. An initial in vitro study using cultured human annulus cells was first performed to test whether there was any difference in identification of senescent cells using the accepted histochemical methodology vs. the immunofluoresent identification of cells positive for senescence-associated-ß-galactosidase in control cells and cells induced into stress-induced premature senescence via hydrogen peroxide exposure. No statistically significant difference was found between the 2 methods. Laser capture microdissection was used to separately harvest senescent and non-senescent cells from 11 human annulus specimens, and microarray analysis was used to determine gene expression levels. Genes with established relationships to senescence were found to be significantly upregulated in senescent cells vs. non-senescent cells. Additional genes related to cytokines, cell proliferation, and other cell processes were also identified. Disc Tissue samples were obtained from surgical disc procedures performed on patients with herniated discs and degenerative disc disease. Tissue was fixed and paraffin embedded. Standard laser capture microdissection (LCM) techniques were used to collect senescent cells. Remaining non-senescent cells were scraped from the histology slide. Total RNA was isolated and analyzed via mircoarray. Gene expression from senescent cells was compared to non-senescent cells. Eight histological samples were used to obtain both senescent and non-senescent cells. From an additional 3 samples, only senescent cells were harvested.

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The senescence-associated cell surfaceome reveals potential senotherapeutic targets in human and mouse cells

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