Human senescent fibroblasts trigger progressive lung fibrosis in mice.

Autor: Hernandez-Gonzalez F; 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.; School of Medicine, University of Barcelona, Barcelona 08036, Spain., Prats N; Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology (BIST), Barcelona 08028, Spain., Ramponi V; Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology (BIST), Barcelona 08028, Spain., López-Domínguez JA; Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology (BIST), Barcelona 08028, Spain., Meyer K; Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology (BIST), Barcelona 08028, Spain., Aguilera M; Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology (BIST), Barcelona 08028, Spain., Muñoz Martín MI; Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology (BIST), Barcelona 08028, Spain., Martínez D; Department of Pathology, Hospital Clinic, Barcelona 08036, Spain., Agusti A; Department of Pulmonology, Respiratory Institute, Hospital Clinic, Barcelona 08036, Spain.; Instituto de Investigaciones Biomédicas August Pi i Sunyer (IDIBAPS), Barcelona 08036, Spain.; Centro de Investigación Biomédica en Red Enfermedades Respiratorias (CIBERES), Madrid 28029, Spain.; School of Medicine, University of Barcelona, Barcelona 08036, Spain., Faner R; Instituto de Investigaciones Biomédicas August Pi i Sunyer (IDIBAPS), Barcelona 08036, Spain.; Centro de Investigación Biomédica en Red Enfermedades Respiratorias (CIBERES), Madrid 28029, Spain.; School of Medicine, University of Barcelona, Barcelona 08036, Spain., Sellarés J; Department of Pulmonology, Respiratory Institute, Hospital Clinic, Barcelona 08036, Spain.; Instituto de Investigaciones Biomédicas August Pi i Sunyer (IDIBAPS), Barcelona 08036, Spain.; Centro de Investigación Biomédica en Red Enfermedades Respiratorias (CIBERES), Madrid 28029, Spain.; School of Medicine, University of Barcelona, Barcelona 08036, Spain., Pietrocola F; Department of Biosciences and Nutrition, Karolinska Institute, Huddinge 14183, Sweden., Serrano M; Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology (BIST), Barcelona 08028, Spain.; Catalan Institution for Research and Advanced Studies (ICREA), Barcelona 08010, Spain.; Altos Labs, Cambridge Institute of Science, Cambridge, United Kingdom.
Jazyk: angličtina
Zdroj: Aging [Aging (Albany NY)] 2023 Jul 01; Vol. 15 (14), pp. 6641-6657. Date of Electronic Publication: 2023 Jul 01.
DOI: 10.18632/aging.204825
Abstrakt: 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.
Databáze: MEDLINE
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