Elisabetta Mereu, Diego Balboa, Johannes Liebig, Aitor Gonzalez-Herrero, Anna Martinez Casals, Mariya Mardamshina, Fanny Mollandin, Felix Schicktanz, Alexander Sudy, Luca Tosti, Maarten van Agen, Valerie Vandenbempt, Dana Avrahami, Frederic Ballllosera Navarro, Edgar Bernardo, Frida Björklund, Robert Lorenz Chua, Marten Engelse, Javier García-Hurtado, Nathalie Groen, Maaike Hanegraaf, Pablo Iañez, Katharina Jechow, Björn Konukiewitz, Christian Lawerenz, Nadja Lewandowski-Hoppe, Domenica Marchese, Mauro J Muraro, Silvia Pellegrini, Valeria Sordi, Ulrike Taron, Foo Wei Ten, Timo Trefzer, Sven Twardziok, Johannes Wirth, Françoise Carlotti, Eelco de Koning, Jorge Ferrer, Benjamin Glaser, Holger Heyn, Emma Lundberg, Lorenzo Piemonti, Katja Steiger, Alexander van Oudenaarden, Wilko Weichert, Christian Conrad, Roland Eils
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 single-cell RNA sequencing (scRNA-seq)/single-nucleus RNA sequencing (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 define 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.