Latent plasticity of the human pancreas across development, health, and disease.

Mereu, E.; Balboa, D.; Liebig, J.; Gonzalez-Herrero, A.; Martinez Casals, A.; Mardamshina, M.; Mollandin, F.; Schickentanz, F.; Tosti, L.; Vandenbempt, V.; Avrahami, D.; Bernardo, E.; Bjorklund, F.; Chua, R. L.; Engelse, M.; Garcia-Hurtado, J.; Groen, N.; Hanegraaf, M.; Ianez, P.; Jechow, K.; Konukiewitz, B.; Lawerenz, C.; Marchese, D.; Muraro, M.; Pellegrini, S.; Sordi, V.; Sudy, A.; Taron, U.; Ten, F. W.; Trefzer, T.; Twardziok, S.; van Agen, M.; Carlotti, F.; de Koning, E.; Ferrer, J.; Glaser, B.; Heyn, H.; Lundberg, E.; Piemonti, L.; Steiger, K.; van Oudenaarden, A.; Weichert, W.; Conrad,

doi:10.1101/2025.10.01.679230

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bioRxiv · 10.1101/2025.10.01.679230

Latent plasticity of the human pancreas across development, health, and disease.

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Abstract

The pancreas plays a central role in major human diseases, yet our understanding of its cellular diversity and plasticity remains incomplete. Here, we present a single-cell multiomics atlas of the human pancreas, profiling over four million cells and nuclei from 57 donors across fetal development, adult homeostasis, and type 2 diabetes (T2D). Integrating sc/snRNA-seq, snATAC-seq, VASA-seq, spatial transcriptomics (Xenium), and multiplexed proteomics (CODEX), we resolve gene expression, chromatin accessibility, and spatial organization at high resolution. We identify transcriptionally plastic centroacinar-like cells (pCACs) in adults with fetal-like features, delineate endocrine and exocrine lineage trajectories during development, and uncover HNF1A-defined beta cell epigenetic states. In T2D, we observe shifts in beta cell subtypes and altered regulatory programs. Glucose perturbation of healthy islets reveals cell-type-specific adaptation and stress responses. This atlas provides a foundational framework to understand pancreas biology and the role of cellular plasticity in regeneration and disease.

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Mereu, E., Balboa, D., Liebig, J., Gonzalez-Herrero, A., Martinez Casals, A., Mardamshina, M., Mollandin, F., Schickentanz, F., Tosti, L., Vandenbempt, V., Avrahami, D., Bernardo, E., Bjorklund, F., Chua, R. L., Engelse, M., Garcia-Hurtado, J., Groen, N., Hanegraaf, M., Ianez, P., Jechow, K., Konukiewitz, B., Lawerenz, C., Marchese, D., Muraro, M., Pellegrini, S., Sordi, V., Sudy, A., Taron, U., Ten, F. W., Trefzer, T., Twardziok, S., van Agen, M., Carlotti, F., de Koning, E., Ferrer, J., Glaser, B., Heyn, H., Lundberg, E., Piemonti, L., Steiger, K., van Oudenaarden, A., Weichert, W., Conrad,. 2025-10-03. Latent plasticity of the human pancreas across development, health, and disease.. https://doi.org/10.1101/2025.10.01.679230

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