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Epithelial-fibroblast crosstalk initiates protective mechanisms in epithelial cells upon acute injury

ABSTRACT: Idiopathic pulmonary fibrosis (IPF) is a progressive and lethal lung disease characterized by excessive fibrotic scar tissue accumulation, compromising lung function. While the precise etiology of IPF remains elusive, emerging evidence suggests that sustained lung epithelial injury is a key driver in the disease's development and progression. This persistent injury, unlike normal wound healing, maintains a pro-fibrotic niche that continually fuels the fibrotic process. Consequently, the question remains whether there is a way to alter this niche signaling, counteract the pro-fibrotic signals, and restore physiological wound healing. By approaching an epithelial-fibroblast coculture model, we investigated in the intercellular communication in chronic and acute injury situations. We identified that epithelial cells and fibroblasts together, create a protective niche signaling preventing further damage in acute injuries. Within epithelial cells, we observed that a switch of the metabolic state towards increased aerobic fatty acid metabolism initiates regenerative processes. While delineating secreted regulators responsible for inducing these positive responses, we identified pentraxin 3 (PTX3) as a top hit harboring antifibrotic characteristics. Modifying the niche by addition of PTX3 on chronically injured epithelial cells causes an amelioration of the pro-fibrotic phenotype and maintained the epithelial barrier integrity. These findings offer valuable insights in key differences of acute and chronic injuries and underscore the importance of understanding the complex interplay between epithelial cells and fibroblasts in lung injury and repair.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (ncbitaxon:9606)

SUBMITTER: Matthew J. Thomas

PROVIDER: MSV000097369 | MassIVE | Tue Mar 18 22:08:00 GMT 2025

SECONDARY ACCESSION(S): PXD062012

REPOSITORIES: MassIVE

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Project description:As a group, fibroproliferative disorders of the lung, liver, kidney, heart, vasculature and integument are common, progressive and refractory to therapy. They can emerge following toxic insults, but are frequently idiopathic. Their enigmatic propensity to resist therapy and progress to organ failure has focused attention on the myofibroblast – the primary effector of the fibroproliferative response. A central unanswered question is whether these myofibroblasts have acquired a distinct pathological phenotype - or whether they are normal myofibroblasts with a pathological phenotype that depends upon residing in a sea of pro-fibrotic cytokines and an abnormal extracellular matrix. Using a systems approach to study this question in a prototype fibrotic disease, Idiopathic Pulmonary Fibrosis (IPF); here we show organized changes in the gene expression pathway of primary lung myofibroblasts that persist for up to 9 sub-cultivations in vitro. When comparing IPF and control myofibroblasts in a 3-dimensional type I collagen matrix, more genes differed at the level of ribosome recruitment than at the level of transcript abundance, indicating pathological translational control as a major characteristic of IPF myofibroblasts. To determine the effect of matrix state on translational control, myofibroblasts were permitted to contract the matrix. Ribosome recruitment in control myofibroblasts was relatively stable. In contrast, IPF cells manifested large alterations in the ribosome recruitment pattern. Pathological studies suggest an epithelial origin for IPF myofibroblasts through the epithelial to mesenchymal transition (EMT). In accord with this, we found systems-level indications for TGF?b -driven EMT as one source of IPF myofibroblasts. Keywords: cell type comparison Comparison of lung myofibroblasts from patients with Idiopatic Pulmonary Fibrosis (IPF, 6 donors) to control (6 donors) in contractile and non-contractile matrices using both total and polyribosomal RNA

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Epithelial-fibroblast crosstalk initiates protective mechanisms in epithelial cells upon acute injury

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