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

Elisabetta Mereu; Diego Balboa; Johannes Liebig; A. Herrero; Anna Martinez Casals; Mariya Mardamshina; Fanny Mollandin; Felix Schickentanz; Luca Tosti; Valerie Vandenbempt; Dana Avrahami; Edgar Bernardo; Frida Björklund; Robert Lorenz Chua; Marten A. Engelse; Javier García-Hurtado; Nathalie Gröen; Maaike A. J. Hanegraaf; Pablo Iáñez Picazo; Katharina Jechow; Björn Konukiewitz; Christian Lawerenz; Doménica Marchese; Mauro J. Muraro; Silvia Pellegrini; Valeria Sordi; Alexander Sudy; Ulrike H. Taron; Foo Wei Ten; Timo B. Trefzer

doi:10.1101/2025.10.01.679230

GenomicsbioRxivOct 1, 2025

Preprint

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

Elisabetta Mereu iD, Diego Balboa iD, Johannes Liebig iD, A. Herrero iD, Anna Martinez Casals iD, Mariya Mardamshina iD, Fanny Mollandin iD, Felix Schickentanz, Luca Tosti iD, Valerie Vandenbempt iD, Dana Avrahami iD, Edgar Bernardo iD, Frida Björklund iD, Robert Lorenz Chua iD, Marten A. Engelse iD, Javier García-Hurtado iD, Nathalie Gröen iD, Maaike A. J. Hanegraaf, Pablo Iáñez Picazo iD, Katharina Jechow iD, Björn Konukiewitz iD, Christian Lawerenz, Doménica Marchese iD, Mauro J. Muraro iD, Silvia Pellegrini iD, , Roland Eils iD

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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