Intrinsic Abnormalities of Cystic Fibrosis Airway Connective Tissue Revealed by an In Vitro 3D Stromal Model

Abstract

Cystic fibrosis is characterized by lung dysfunction involving mucus hypersecretion, bacterial infections, and inflammatory response. Inflammation triggers pro-fibrotic signals that compromise lung structure and function. At present, several in vitro cystic fibrosis models have been developed to study epithelial dysfunction but none of these focuses on stromal alterations. Here we show a new cystic fibrosis 3D stromal lung model made up of primary fibroblasts embedded in their own extracellular matrix and investigate its morphological and transcriptomic features. Cystic fibrosis fibroblasts showed a high proliferation rate and produced an abundant and chaotic matrix with increased protein content and elastic modulus. More interesting, they had enhanced pro-fibrotic markers and genes involved in epithelial function and inflammatory response. In conclusion, our study reveals that cystic fibrosis fibroblasts maintain in vitro an activated pro-fibrotic state. This abnormality may play in vivo a role in the modulation of epithelial and inflammatory cell behavior and lung remodeling. We argue that the proposed bioengineered model may provide new insights on epithelial/stromal/inflammatory cells crosstalk in cystic fibrosis, paving the way for novel therapeutic strategies.

Cystic fibrosis transmembrane conductance regulator in COPD: a role in respiratory epithelium and beyond

“…A CF stromal lung model based on fibroblasts from patients with CF found that fibroblasts maintain an activated pro-fibrotic state in vitro and a high proliferation rate. Furthermore, this model showed enhanced pro-fibrotic markers and upregulation of genes involved in epithelial function and inflammatory response [ 57 ]. In patients with COPD, fibroblasts demonstrate decreased capacity for sustaining tissue repair [ 58 ].…”

Modeling pulmonary cystic fibrosis in a human lung airway-on-a-chip

“…Additional cell types, such as pulmonary macrophages and lung fibroblasts, are also missing from the model, and they could be added in the future as well. Indeed, the pathogenetic relevance of the airway connective tissue has been recently documented in a 3D CF stromal lung model [30]. It is possible that the absence of some or all of these CF patient-derived cells could contribute to the explanation of why we did not observe .…”

3D Lung Tissue Models for Studies on SARS-CoV-2 Pathophysiology and Therapeutics

“…In addition, transwell cultures allow the investigation of the interactions among cell and tissue types, pathogens and the immune system [ 30 , 31 , 32 ]. These models have been extensively exploited to study CF, chronic obstructive pulmonary disease (COPD) and airway infections by bacterial and viral pathogens [ 33 , 34 , 35 , 36 ].…”