Chronic respiratory diseases are the third leading cause of death for those above the age of 65, making it an age-related disease. With an aging domestic population where 1 in 4 Americans will be over 65 years of age by 2050, the prevalence of age-related disease is expected to increase. Cellular senescence is a natural response to DNA damage, which prevents malignant transformation by permanently arresting the cell cycle. However, senescent cells accumulate in the tissue with age, and this accumulation has been shown to mediate pulmonary fibrosis and the subsequent decline in organ function. This study investigates fibroblast senescence-associated extracellular matrix (ECM) remodeling and its ability to promote a pathological senescent matrix architecture. γ-irradiation was used to induce a senescent phenotype and was validated using β-galactosidase staining, fluorescent microscopy, cell phenotype characterization, and qRT-PCR. Fibroblast-derived matrices (FDM) were grown using pre-senescent and senescent pulmonary fibroblasts over 21 days. Using second-harmonic generation microscopy to characterize collagen fiber organization, we found that senescent matrix collagen fibers were more disorganized globally and locally than the pre-senescent (non-senescent) architectures. Through inhibition of the TGF-β pathway, we found that we were able to decrease local senescent fiber disorganization back to pre-senescent levels. Our findings suggest senescent FDMs undergo a remodeling process that results in a pro-fibrotic ECM architecture, which explains how the accumulation of cellular senescence has a developmental role in fibrosis. We also found that this disorganized architecture can be targeted therapeutically to resolve pathological senescent matrix alterations, and this research may eventually have implications for targeted treatments related to pulmonary fibrosis and age-related disease.
Dea, Nova, Howes, Andrew, Ghosh, Deepraj, et al.,
"Senescent Fibroblast Matrix Remodeling Promotes Fibrotic Lung Architecture"
(2023).
Summer Research Symposium.
Brown Digital Repository. Brown University Library.
https://doi.org/10.26300/d0tk-9p94
Each year, Brown University showcases the research of its undergraduates at the Summer Research Symposium. More than half of the student-researchers are UTRA recipients, while others receive funding from a variety of Brown-administered and national programs and fellowships and go …
