CCR10 ⁺ epithelial cells from idiopathic pulmonary fibrosis lungs drive remodeling

Abstract

Idiopathic pulmonary fibrosis (IPF) is a devastating fibrotic lung disease of unknown etiology and limited therapeutic options. In this report, we characterize what we believe is a novel CCR10 ⁺ epithelial cell population in IPF lungs. There was a significant increase in the percentage of CCR10 ⁺ epithelial cells in IPF relative to normal lung explants and their numbers significantly correlated to lung remodeling in humanized NSG mice. Cultured CCR10-enriched IPF epithelial cells promoted IPF lung fibroblast invasion and collagen 1 secretion. Single-cell RNA sequencing analysis showed distinct CCR10 ⁺ epithelial cell populations enriched for inflammatory and profibrotic transcripts. Consistently, cultured IPF but not normal epithelial cells induced lung remodeling in humanized NSG mice, where the number of CCR10 ⁺ IPF, but not normal, epithelial cells correlated with hydroxyproline concentration in the remodeled NSG lungs. A subset of IPF CCR10 ^hi epithelial cells coexpress EphA3 and ephrin A signaling induces the expression of CCR10 by these cells. Finally, EphA3 ⁺CCR10 ^hi epithelial cells induce more consistent lung remodeling in NSG mice relative to EphA3 ^–CCR10 ^lo epithelial cells. Our results suggest that targeting epithelial cells, highly expressing CCR10, may be beneficial in IPF.

Abstract

CCR10+ epithelial cells are abundantly detected in lungs from IPF patients, where these cells promote IPF lung fibroblast invasion, collagen 1 secretion, and lung fibrosis in humanized mice.