ILC2s regulate a fibroblast progenitor niche in the pancreas
- Thomas Yip
- Julie Stockis
- Charlotte Simpson
- Erika E. McCartney
- Shwetha Raghunathan
- Martha M. Rangel-Sosa
- Sydney N. Hummel
- Julia Moreno-Vicente
- Gianmarco Raddi
- Celine Garcia
- Rugile Linkute
- Silvain Pinaud
- Maye F. Cheng
- Lesley A. Hill
- T. Michael Underhill
- Hans-Reimer Rodewald
- Christoph Schneider
- Claus Jørgensen
- Andrew N.J. McKenzie
- Sophie E. Acton
- Patrick Seale
- Menna R. Clatworthy
- Matthew B. Buechler
- Timotheus Y. F. Halim
2026-07-02
Local fibroblast development and densities influence organ health and disease, although it remains unclear how tissue fibroblast topography is controlled in situ. Here, we defined Group 2 innate lymphoid cells (ILC2s) as key regulators of fibroblast homeostasis in the pancreas. ILC2s colocalized with fibroblasts expressing the genes Pi16 + Dpp4 + Ly6c + in an interstitial niche of the exocrine pancreas, which encapsulates the organ parenchyma. ILC2s specifically regulated the expansion of Pi16 + Dpp4 + Ly6c + fibroblasts, which have progenitor capacity, while restraining differentiated intraparenchymal Col15a1 + fibroblasts during inflammation. These circuits reinforced fibroblast numbers after injury and set an inflammatory threshold. The ILC2 and Pi16 + Dpp4 + Ly6c + fibroblast progenitor niche expanded around tumors and controlled cancer-associated fibroblast ontogeny and density. Hence, ILC2-fibroblast dialogue represents a regulatory node that locally orchestrates tissue homeostasis and pathology.