Human Senescent Fibroblasts Trigger Progressive Lung Fibrosis in Mice | Aging-US

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Aging-US published this research paper as the cover for Volume 15, Issue 14, entitled, "Human senescent fibroblasts trigger progressive lung fibrosis in mice" by researchers from the Department of Pulmonology, Respiratory Institute, Hospital Clinic, Barcelona 08036, Spain; Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology (BIST), Barcelona 08028, Spain; Instituto de Investigaciones Biomédicas August Pi i Sunyer (IDIBAPS), Barcelona 08036, Spain; Department of Pathology, Hospital Clinic, Barcelona 08036, Spain; Centro de Investigación Biomédica en Red Enfermedades Respiratorias (CIBERES), Madrid 28029, Spain; School of Medicine, University of Barcelona, Barcelona 08036, Spain; Department of Biosciences and Nutrition, Karolinska Institute, Huddinge 14183, Sweden; Catalan Institution for Research and Advanced Studies (ICREA), Barcelona 08010, Spain; Altos Labs, Cambridge Institute of Science, Cambridge, United Kingdom. DOI - https://doi.org/10.18632/aging.204825 Corresponding authors - Manuel Serrano - mserrano@altoslabs.com (https://orcid.org/0000-0001-7177-9312), and Federico Pietrocola - federico.pietrocola@ki.se (https://orcid.org/0000-0002-2930-234X) Abstract Cell senescence has recently emerged as a potentially relevant pathogenic mechanism in fibrosing interstitial lung diseases (f-ILDs), particularly in idiopathic pulmonary fibrosis. We hypothesized that senescent human fibroblasts may suffice to trigger a progressive fibrogenic reaction in the lung. To address this, senescent human lung fibroblasts, or their secretome (SASP), were instilled into the lungs of immunodeficient mice. We found that: (1) 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; (2) 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; and, (3) navitoclax, nintedanib and pirfenidone ameliorate lung fibrosis induced by senescent human fibroblasts in mice, albeit 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. Sign up for free Altmetric alerts about this article - https://aging.altmetric.com/details/email_updates?id=10.18632%2Faging.204825 Subscribe for free publication alerts from Aging - https://www.aging-us.com/subscribe-to-toc-alerts Keywords - aging, mouse model, cellular senescence, pulmonary fibrosis, antifibrotics, senolytic About Aging-US Launched in 2009, Aging-US publishes papers of general interest and biological significance in all fields of aging research and age-related diseases, including cancer—and now, with a special focus on COVID-19 vulnerability as an age-dependent syndrome. Topics in Aging-US go beyond traditional gerontology, including, but not limited to, cellular and molecular biology, human age-related diseases, pathology in model organisms, signal transduction pathways (e.g., p53, sirtuins, and PI-3K/AKT/mTOR, among others), and approaches to modulating these signaling pathways. Please visit our website at https://www.Aging-US.com​​ and connect with us: SoundCloud - https://soundcloud.com/Aging-Us Facebook - https://www.facebook.com/AgingUS/ Twitter - https://twitter.com/AgingJrnl Instagram - https://www.instagram.com/agingjrnl/ YouTube - https://www.youtube.com/@AgingJournal LinkedIn - https://www.linkedin.com/company/aging/ Pinterest - https://www.pinterest.com/AgingUS/ Media Contact 18009220957 MEDIA@IMPACTJOURNALS.COM