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

Elisabetta Mereu; Diego Balboa; Johannes Liebig; Aitor Gonzalez-Herrero; Anna Martinez-Casals; Mariya Mardamshina; Fanny Mollandin; Felix Schicktanz; Luca Tosti; Valerie Vandenbempt; Dana Avrahami; Edgar Bernardo; Frida Björklund; Robert Lorenz Chua; Marten Engelse; Javier García-Hurtado; Nathalie Groen; Maaike Hanegraaf; Pablo Iañez; Katharina Jechow; Björn Konukiewitz; Christian Lawerenz; Domenica Marchese; Mauro J Muraro; Silvia Pellegrini; Valeria Sordi; Alexander Sudy; Ulrike Taron; Foo Wei Ten; Timo Trefzer; Sven Twardziok; Maarten van Agen; 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

doi:10.1101/2025.10.01.679230

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

Elisabetta Mereu^*, Diego Balboa, Johannes Liebig, Aitor Gonzalez-Herrero, Anna Martinez-Casals, Mariya Mardamshina, Fanny Mollandin, Felix Schicktanz, Luca Tosti, Valerie Vandenbempt, Dana Avrahami, Edgar Bernardo, Frida Björklund, Robert Lorenz Chua, Marten Engelse, Javier García-Hurtado, Nathalie Groen, Maaike Hanegraaf, Pablo Iañez, Katharina JechowBjörn Konukiewitz, Christian Lawerenz, Domenica Marchese, Mauro J Muraro, Silvia Pellegrini, Valeria Sordi, Alexander Sudy, Ulrike Taron, Foo Wei Ten, Timo Trefzer, Sven Twardziok, Maarten van Agen, 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^*

^*Corresponding author for this work

Research output: Working paper › Preprint › Academic

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.

Original language	English
Publisher	BioRxiv
Number of pages	32
DOIs	https://doi.org/10.1101/2025.10.01.679230
Publication status	Published - 3 Oct 2025

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Latent plasticity of the human pancreas across development, health, and diseaseSubmitted manuscript, 15 MBLicence: CC BY-NC-ND

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Mereu, E., Balboa, D., Liebig, J., Gonzalez-Herrero, A., Martinez-Casals, A., Mardamshina, M., Mollandin, F., Schicktanz, F., Tosti, L., Vandenbempt, V., Avrahami, D., Bernardo, E., Björklund, F., Chua, R. L., Engelse, M., García-Hurtado, J., Groen, N., Hanegraaf, M., Iañez, P., ... Eils, R. (2025). Latent plasticity of the human pancreas across development, health, and disease. BioRxiv. https://doi.org/10.1101/2025.10.01.679230

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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.",

author = "Elisabetta Mereu and Diego Balboa and Johannes Liebig and Aitor Gonzalez-Herrero and Anna Martinez-Casals and Mariya Mardamshina and Fanny Mollandin and Felix Schicktanz and Luca Tosti and Valerie Vandenbempt and Dana Avrahami and Edgar Bernardo and Frida Bj{\"o}rklund and Chua, \{Robert Lorenz\} and Marten Engelse and Javier Garc{\'i}a-Hurtado and Nathalie Groen and Maaike Hanegraaf and Pablo Ia{\~n}ez and Katharina Jechow and Bj{\"o}rn Konukiewitz and Christian Lawerenz and Domenica Marchese and Muraro, \{Mauro J\} and Silvia Pellegrini and Valeria Sordi and Alexander Sudy and Ulrike Taron and Ten, \{Foo Wei\} and Timo Trefzer and Sven Twardziok and \{van Agen\}, Maarten and Fran{\c c}oise Carlotti and \{de Koning\}, Eelco and Jorge Ferrer and Benjamin Glaser and Holger Heyn and Emma Lundberg and Lorenzo Piemonti and Katja Steiger and \{van Oudenaarden\}, Alexander and Wilko Weichert and Christian Conrad and Roland Eils",

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Mereu, E, Balboa, D, Liebig, J, Gonzalez-Herrero, A, Martinez-Casals, A, Mardamshina, M, Mollandin, F, Schicktanz, F, Tosti, L, Vandenbempt, V, Avrahami, D, Bernardo, E, Björklund, F, Chua, RL, Engelse, M, García-Hurtado, J, Groen, N, Hanegraaf, M, Iañez, P, Jechow, K, Konukiewitz, B, Lawerenz, C, Marchese, D, Muraro, MJ, Pellegrini, S, Sordi, V, Sudy, A, Taron, U, Ten, FW, 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, C & Eils, R 2025 'Latent plasticity of the human pancreas across development, health, and disease' BioRxiv. https://doi.org/10.1101/2025.10.01.679230

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T1 - Latent plasticity of the human pancreas across development, health, and disease

AU - Mereu, Elisabetta

AU - Balboa, Diego

AU - Liebig, Johannes

AU - Gonzalez-Herrero, Aitor

AU - Martinez-Casals, Anna

AU - Mardamshina, Mariya

AU - Mollandin, Fanny

AU - Schicktanz, Felix

AU - Tosti, Luca

AU - Vandenbempt, Valerie

AU - Avrahami, Dana

AU - Bernardo, Edgar

AU - Björklund, Frida

AU - Chua, Robert Lorenz

AU - Engelse, Marten

AU - García-Hurtado, Javier

AU - Groen, Nathalie

AU - Hanegraaf, Maaike

AU - Iañez, Pablo

AU - Jechow, Katharina

AU - Konukiewitz, Björn

AU - Lawerenz, Christian

AU - Marchese, Domenica

AU - Muraro, Mauro J

AU - Pellegrini, Silvia

AU - Sordi, Valeria

AU - Sudy, Alexander

AU - Taron, Ulrike

AU - Ten, Foo Wei

AU - Trefzer, Timo

AU - Twardziok, Sven

AU - van Agen, Maarten

AU - Carlotti, Françoise

AU - de Koning, Eelco

AU - Ferrer, Jorge

AU - Glaser, Benjamin

AU - Heyn, Holger

AU - Lundberg, Emma

AU - Piemonti, Lorenzo

AU - Steiger, Katja

AU - van Oudenaarden, Alexander

AU - Weichert, Wilko

AU - Conrad, Christian

AU - Eils, Roland

PY - 2025/10/3

Y1 - 2025/10/3

N2 - 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.

AB - 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.

U2 - 10.1101/2025.10.01.679230

DO - 10.1101/2025.10.01.679230

M3 - Preprint

C2 - 41256699

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

PB - BioRxiv

ER -

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

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