Pancreatic Plasticity in Development and Disease : Nat Rev Gastroenterol Hepatol | May 2026

Introduction

The pancreas represents one of the most dynamic models of cellular plasticity in human biology, where developmental fate decisions, tissue maintenance and regenerative responses are orchestrated through tightly regulated transcriptional and microenvironmental interactions. Recent advances in single-cell sequencing, spatial transcriptomics and lineage-tracing technologies have transformed understanding of pancreatic ontogeny, uncovering previously unrecognized cellular heterogeneity and transient developmental states. Pancreatic Cancer and Diabetes have increasingly been linked to dysregulated cellular plasticity pathways that recapitulate embryonic developmental programs.

Problem Statement

Despite major progress in defining pancreatic cell lineages, the mechanisms governing lineage commitment, dedifferentiation and regeneration remain incompletely understood. The relationship between developmental plasticity and pathological reprogramming in adult pancreatic tissue is particularly important, as injury-induced or disease-associated plasticity may contribute both to tissue repair and malignant transformation. Understanding how pancreatic cell identity is established and destabilized is critical for advancing regenerative medicine, stem-cell–based therapies and novel therapeutic strategies for pancreatic diseases.

Summary

This review provides an integrated overview of pancreatic development and cellular plasticity across embryogenesis, tissue homeostasis and disease. Pancreatic organogenesis is presented as a highly coordinated process involving reciprocal signalling between pancreatic endoderm and surrounding mesenchymal, endothelial, neural and immune compartments. These interactions are integrated through complex gene regulatory networks governed by lineage-defining transcription factors that determine endocrine, acinar and ductal cell fates. Single-cell and spatial analyses have identified substantial cellular diversity within pancreatic tissue, including rare and transient intermediate states that appear critical for lineage specification and adaptive remodelling. The review highlights how developmental plasticity mechanisms persist into adulthood, where they may become reactivated during injury, inflammation and neoplastic transformation. In particular, adult pancreatic cells can undergo dedifferentiation and lineage conversion in response to stress, resembling embryonic transcriptional programs. Such plasticity may support tissue regeneration but can also facilitate tumorigenesis in pancreatic cancer. Importantly, insights derived from developmental biology have enabled the generation of pancreatic cell types from human pluripotent stem cells, advancing the field of regenerative therapeutics for diabetes and pancreatic disorders. Emerging in vitro systems that better reproduce pancreatic microenvironmental niches and multicellular interactions are now providing increasingly physiologic platforms for disease modelling and therapeutic development. Overall, the review positions cellular plasticity as a central biological principle linking pancreatic development, regeneration and disease pathogenesis, with major implications for future translational strategies.