ILC2s regulate a fibroblast progenitor niche in the pancreas.

Abstract

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 <i>Pi16⁺Dpp4⁺Ly6c⁺</i> in an interstitial niche of the exocrine pancreas, which encapsulates the organ parenchyma. ILC2s specifically regulated the expansion of <i>Pi16⁺Dpp4⁺Ly6c⁺</i> fibroblasts, which have progenitor capacity, while restraining differentiated intraparenchymal <i>Col15a1⁺</i> fibroblasts during inflammation. These circuits reinforced fibroblast numbers after injury and set an inflammatory threshold. The ILC2 and <i>Pi16⁺Dpp4⁺Ly6c⁺</i> 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.