A human and mouse subpopulation of senescent β-cells induces pathologic dysfunction through targetable paracrine signaling

Iwasaki, K.; Carapeto, P.; Abarca, C.; Hela, F.; Sanjines, S.; Pena, S.; Le, S.; Pan, H.; Cahill, C.; Midha, A.; Diniz, J. A.; Baker, D.; Domanskyi, S.; Espinoza, S.; Pena, A.; Cigarroa, F. G.; Woolworth, J. L.; Chuang, J. H.; Garovic, V. D.; Kirkland, J.; Tchkonia, T.; Musi, N.; Kuchel, G. A.; Robson, P.; Aguayo-Mazzucato, C.

doi:10.1101/2025.05.07.648438

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bioRxiv · 10.1101/2025.05.07.648438

A human and mouse subpopulation of senescent β-cells induces pathologic dysfunction through targetable paracrine signaling

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Abstract

Cellular senescence is a stress response mechanism marked by irreversible growth arrest, upregulation of antiapoptotic pathways, loss of cellular function, and remodelling of the cellular secretory profile. In both humans and mice, pancreatic {beta}-cells undergo senescence with age and insulin resistance. Targeted removal of senescent cells in mouse models of diabetes improves glucose homeostasis, demonstrating the role {beta}-cell senescence in diabetes progression. In contrast, {beta}-cell senescence also promotes immune surveillance, promoting {beta}-cell survival and function. Thus, a better understanding of senescent cells phenotypic and functional heterogeneity is needed to develop effective therapeutic strategies. Herein, we show that subpopulations of senescent {beta}-cells in mice and humans, which were identified through the expression of Cdkn1a (encoding p21Cip1) and Cdkn2a (encoding p16Ink4a) by single-cell RNA sequencing (scRNA-seq), flow cytometry, spatial transcriptomics, and spatial proteomics, exhibit distinct transcriptional and functional identities. The predominant senescent {beta}-cell subpopulation expressed Cdkn1a and was characterized by a lack of glucose responsiveness, high basal insulin secretion, and transcription of canonical SASP factors. The SASP of Cdkn1a-expressing {beta}-cells had non-cell autonomous effects on neighbouring cells. A subset of four SASP factors from Cdkn1a+ cells was sufficient to induce secondary senescence and {beta}-cell dysfunction in vitro. JAK inhibitors (JAK1/2 and JAK1/3) counteracted secondary senescence induction and restored {beta}-cell function in high-fat diet-fed mice and human islets from donors with or without type 2 diabetes. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=196 SRC="FIGDIR/small/648438v1_ufig1.gif" ALT="Figure 1"> View larger version (34K): org.highwire.dtl.DTLVardef@9b8addorg.highwire.dtl.DTLVardef@1b9c4eborg.highwire.dtl.DTLVardef@12f2964org.highwire.dtl.DTLVardef@1468297_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Iwasaki, K., Carapeto, P., Abarca, C., Hela, F., Sanjines, S., Pena, S., Le, S., Pan, H., Cahill, C., Midha, A., Diniz, J. A., Baker, D., Domanskyi, S., Espinoza, S., Pena, A., Cigarroa, F. G., Woolworth, J. L., Chuang, J. H., Garovic, V. D., Kirkland, J., Tchkonia, T., Musi, N., Kuchel, G. A., Robson, P., Aguayo-Mazzucato, C.. 2025-05-07. A human and mouse subpopulation of senescent β-cells induces pathologic dysfunction through targetable paracrine signaling. https://doi.org/10.1101/2025.05.07.648438

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