Human Senescent Fibroblasts Cause Lung Fibrosis in Mice
07-31-2023“These observations support that accumulation of senescent cells may contribute to fibrotic lung disease [...]”
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BUFFALO, NY- July 31, 2023 – A new research paper was published on the cover of Aging (listed by MEDLINE/PubMed as "Aging (Albany NY)" and "Aging-US" by Web of Science) Volume 15, Issue 14, entitled, “Human senescent fibroblasts trigger progressive lung fibrosis in mice.”
Cell senescence has recently emerged as a potentially relevant pathogenic mechanism in fibrosing interstitial lung diseases (f-ILDs), particularly in idiopathic pulmonary fibrosis. In a new study, researchers Fernanda Hernandez-Gonzalez, Neus Prats, Valentina Ramponi, José Alberto López-Domínguez, Kathleen Meyer, Mònica Aguilera, María Isabel Muñoz Martín, Daniel Martínez, Alvar Agusti, Rosa Faner, Jacobo Sellarés, Federico Pietrocola, and Manuel Serrano from Hospital Clinic Barcelona, The Barcelona Institute of Science and Technology (BIST), Instituto de Investigaciones Biomédicas August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red Enfermedades Respiratorias (CIBERES), University of Barcelona, Karolinska Institute, Catalan Institution for Research and Advanced Studies (ICREA), and Altos Labs hypothesized that senescent human fibroblasts may suffice to trigger a progressive fibrogenic reaction in the lung.
“Here we: (1) explored this hypothesis in vivo; (2) investigated the potential underlying biological mechanisms in vitro; and (3) studied the effects of one experimental senolytic compound (navitoclax) and two anti-fibrotic drugs currently used in the treatment of IPF in humans (nintedanib and pirfenidone), both in vivo and in vitro.”
To address this, senescent human lung fibroblasts, or their secretome (SASP), were instilled into the lungs of immunodeficient mice. The researchers found that human senescent fibroblasts engraft in the lungs of immunodeficient mice and trigger progressive lung fibrosis associated to increasing levels of mouse senescent cells, whereas non-senescent fibroblasts do not trigger fibrosis. They also found that the SASP of human senescent fibroblasts is pro-senescence and pro-fibrotic both in vitro when added to mouse recipient cells and in vivo when delivered into the lungs of mice, whereas the conditioned medium (CM) from non-senescent fibroblasts lacks these activities. Finally, navitoclax, nintedanib and pirfenidone were found to ameliorate lung fibrosis induced by senescent human fibroblasts in mice, while only navitoclax displayed senolytic activity.
“We conclude that human senescent fibroblasts, through their bioactive secretome, trigger a progressive fibrogenic reaction in the lungs of immunodeficient mice that includes the induction of paracrine senescence in the cells of the host, supporting the concept that senescent cells actively contribute to disease progression in patients with f-ILDs.”
Read the full study: DOI: https://doi.org/10.18632/aging.204825
Corresponding Authors: Manuel Serrano, Federico Pietrocola - mserrano@altoslabs.com, federico.pietrocola@ki.se
Keywords: mouse model, cellular senescence, pulmonary fibrosis, antifibrotics, senolytic
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About Aging-US:
Aging publishes research papers in all fields of aging research including but not limited, aging from yeast to mammals, cellular senescence, age-related diseases such as cancer and Alzheimer’s diseases and their prevention and treatment, anti-aging strategies and drug development and especially the role of signal transduction pathways such as mTOR in aging and potential approaches to modulate these signaling pathways to extend lifespan. The journal aims to promote treatment of age-related diseases by slowing down aging, validation of anti-aging drugs by treating age-related diseases, prevention of cancer by inhibiting aging. Cancer and COVID-19 are age-related diseases.
Aging is indexed by PubMed/Medline (abbreviated as “Aging (Albany NY)”), PubMed Central, Web of Science: Science Citation Index Expanded (abbreviated as “Aging‐US” and listed in the Cell Biology and Geriatrics & Gerontology categories), Scopus (abbreviated as “Aging” and listed in the Cell Biology and Aging categories), Biological Abstracts, BIOSIS Previews, EMBASE, META (Chan Zuckerberg Initiative) (2018-2022), and Dimensions (Digital Science).
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