A Single-Cell Atlas of the Murine Pancreatic Ductal Tree Identifies Novel Cell Populations With Potential Implications in Pancreas Regeneration and Exocrine Pathogenesis

Authors

• Ángel Fernández
• Joan Casamitjana
• Adrián Holguín-Horcajo
• Katarina Coolens
• Loris Mularoni
• Li Guo
• Olga Hartwig
• Tim Düking
• Noemi Vidal
• Lincoln N Strickland
• Lorenzo Pasquali
• Jennifer M Bailey-Lundberg
• Ilse Rooman
• Yue J Wang
• Meritxell Rovira

Language

English

Publication Date

10-1-2024

Journal

Gastroenterology

DOI

10.1053/j.gastro.2024.06.008

PMID

38908487

Abstract

Background & aims: Pancreatic ducts form an intricate network of tubules that secrete bicarbonate and drive acinar secretions into the duodenum. This network is formed by centroacinar cells, terminal, intercalated, intracalated ducts, and the main pancreatic duct. Ductal heterogeneity at the single-cell level has been poorly characterized; therefore, our understanding of the role of ductal cells in pancreas regeneration and exocrine pathogenesis has been hampered by the limited knowledge and unexplained diversity within the ductal network.

Methods: We used single cell RNA sequencing to comprehensively characterize mouse ductal heterogeneity at single-cell resolution of the entire ductal epithelium from centroacinar cells to the main duct. Moreover, we used organoid cultures, injury models, and pancreatic tumor samples to interrogate the role of novel ductal populations in pancreas regeneration and exocrine pathogenesis.

Results: We have identified the coexistence of 15 ductal populations within the healthy pancreas and characterized their organoid formation capacity and endocrine differentiation potential. Cluster isolation and subsequent culturing let us identify ductal cell populations with high organoid formation capacity and endocrine and exocrine differentiation potential in vitro, including a Wnt-responsive population, a ciliated population, and Flrt3+ cells. Moreover, we have characterized the location of these novel ductal populations in healthy pancreas, chronic pancreatitis, and tumor samples. The expression of Wnt-responsive, interferon-responsive, and epithelial-to-mesenchymal transition population markers increases in chronic pancreatitis and tumor samples.

Conclusions: In light of our discovery of previously unidentified ductal populations, we unmask potential roles of specific ductal populations in pancreas regeneration and exocrine pathogenesis. Thus, novel lineage-tracing models are needed to investigate ductal-specific populations in vivo.

Keywords

Animals, Pancreatic Ducts, Single-Cell Analysis, Regeneration, Mice, Organoids, Pancreas, Exocrine, Pancreatic Neoplasms, Cell Differentiation, Humans, RNA-Seq, Disease Models, Animal, Cell Lineage, Ceruletide, Ductal Cells, Exocrine Pathologies, Organoids, Pancreas Regeneration, scRNA-Seq

Published Open-Access

yes

Recommended Citation

Fernández, Ángel; Casamitjana, Joan; Holguín-Horcajo, Adrián; et al., "A Single-Cell Atlas of the Murine Pancreatic Ductal Tree Identifies Novel Cell Populations With Potential Implications in Pancreas Regeneration and Exocrine Pathogenesis" (2024). Faculty, Staff and Student Publications. 3410.
https://digitalcommons.library.tmc.edu/uthmed_docs/3410