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Idiopathic pulmonary fibrosis (IPF) is an age-associated disorder characterized by progressive fibrosis of lung tissue, with TGF-β1 acting as a critical pro-fibrotic factor. Recent studies highlight that epithelial-fibroblast crosstalk, particularly involving senescent lung epithelial (LE) cells, plays a pivotal role in fibrosis progression. Moreover, the extracellular matrix (ECM) and tissue architecture significantly influence cellular behavior and responses to fibrotic stimuli. Despite this, the role of ECM dynamics and 3D culture systems in modeling epithelial-fibroblast interactions and fibrotic progression remains underexplored. This study investigates how senescent LE cells influence lung fibroblasts (LF) in co-culture and examines fibrotic responses in both 2D and 3D culture models, aiming to provide insights into fibrosis mechanisms and the impact of ECM architecture.
Senescent and non-senescent lung epithelial (LE) cells were co-cultured with lung fibroblasts (LF) and stimulated with TGF-β1 to assess fibrosis-associated gene expression over 48 hours. Monocultures of LE and LF cells were similarly stimulated to evaluate their individual contributions to fibrotic responses. Gene expression analyses were conducted to compare the effects of senescent versus non-senescent LE cells in co-culture. Additionally, 2D and 3D (alginate/gelatin hydrogel) culture systems were utilized to examine the influence of extracellular matrix (ECM) and 3D architecture on cellular behavior and fibrosis progression.
Senescent LE cells in co-culture enhanced the fibrotic response of LF cells, particularly under TGF-β1 stimulation, supporting the role of epithelial-fibroblast crosstalk in fibrosis progression. In contrast, non-senescent LE cells exerted a protective effect, significantly reducing fibrosis-associated gene expression in LF co-cultures compared to LF monocultures, even after 48 hours of TGF-β1 stimulation. This protective effect underscores the importance of epithelial integrity in modulating fibroblast activation.
In 3D cultures, fibrotic responses were delayed or attenuated compared to 2D models, highlighting the significant influence of ECM dynamics and 3D architecture on cell behavior. These findings emphasize the limitations of 2D models and the potential of 3D systems to provide physiologically relevant insights into IPF pathogenesis.
This study demonstrates that senescent LE cells amplify pro-fibrotic responses in LF cells, while non-senescent LE cells mitigate these effects, underscoring the critical role of epithelial health in fibrosis progression. Furthermore, the delayed fibrotic response observed in 3D culture models highlights the importance of ECM and 3D architecture in modulating cellular behavior. These findings advocate for the use of 3D models to better study IPF mechanisms and evaluate therapeutic interventions. Future research into matrix remodeling markers and epithelial-fibroblast interactions is essential to develop effective fibrosis management strategies.
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