A new mouse model of radiation-induced liver disease reveals mitochondrial dysfunction as an underlying fibrotic stimulus
Nicolas Melin,
Tural Yarahmadov,
Daniel Sanchez-Taltavull,
Fabienne E. Birrer,
Tess M. Brodie,
Benoît Petit,
Andrea Felser,
Jean-Marc Nuoffer,
Matteo Montani,
Marie-Catherine Vozenin,
Evelyn Herrmann,
Daniel Candinas,
Daniel M. Aebersold,
Deborah Stroka
Affiliations
Nicolas Melin
Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, Switzerland; Department for BioMedical Research, Visceral Surgery and Medicine, University of Bern, Switzerland
Tural Yarahmadov
Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, Switzerland; Department for BioMedical Research, Visceral Surgery and Medicine, University of Bern, Switzerland
Daniel Sanchez-Taltavull
Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, Switzerland; Department for BioMedical Research, Visceral Surgery and Medicine, University of Bern, Switzerland
Fabienne E. Birrer
Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, Switzerland; Department for BioMedical Research, Visceral Surgery and Medicine, University of Bern, Switzerland
Tess M. Brodie
Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, Switzerland; Department for BioMedical Research, Visceral Surgery and Medicine, University of Bern, Switzerland
Benoît Petit
Laboratory of Radiation Oncology, Radiation Oncology Service, Department of Oncology, CHUV, Lausanne University Hospital, University of Lausanne, Switzerland
Andrea Felser
Institute of Clinical Chemistry, University of Bern, Switzerland
Jean-Marc Nuoffer
Institute of Clinical Chemistry, University of Bern, Switzerland
Matteo Montani
Department of Pathology, University of Bern, Switzerland
Marie-Catherine Vozenin
Laboratory of Radiation Oncology, Radiation Oncology Service, Department of Oncology, CHUV, Lausanne University Hospital, University of Lausanne, Switzerland
Evelyn Herrmann
Department of Radiation Oncology, Department for BioMedical Research, University of Bern, Bern University Hospital, Switzerland
Daniel Candinas
Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, Switzerland
Daniel M. Aebersold
Department of Radiation Oncology, Department for BioMedical Research, University of Bern, Bern University Hospital, Switzerland
Deborah Stroka
Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, Switzerland; Department for BioMedical Research, Visceral Surgery and Medicine, University of Bern, Switzerland; Corresponding author. Address: Department of Visceral Surgery and Medicine, University of Bern, Murtenstrasse 35, 3008 Bern, Switzerland; Tel.: +41 (0)31 632 27 48..
Background & Aims: High-dose irradiation is an essential tool to help control the growth of hepatic tumors, but it can cause radiation-induced liver disease (RILD). This life-threatening complication manifests itself months following radiation therapy and is characterized by fibrosis of the pericentral sinusoids. In this study, we aimed to establish a mouse model of RILD to investigate the underlying mechanism of radiation-induced liver fibrosis. Methods: Using a small animal image-guided radiation therapy platform, an irradiation scheme delivering 50 Gy as a single dose to a focal point in mouse livers was designed. Tissues were analyzed 1 and 6 days, and 6 and 20 weeks post-irradiation. Irradiated livers were assessed by histology, immunohistochemistry, imaging mass cytometry and RNA sequencing. Mitochondrial function was assessed using high-resolution respirometry. Results: At 6 and 20 weeks post-irradiation, pericentral fibrosis was visible in highly irradiated areas together with immune cell infiltration and extravasation of red blood cells. RNA sequencing analysis showed gene signatures associated with acute DNA damage, p53 activation, senescence and its associated secretory phenotype and fibrosis. Moreover, gene profiles of mitochondrial damage and an increase in mitochondrial DNA heteroplasmy were detected. Respirometry measurements of hepatocytes in vitro confirmed irradiation-induced mitochondrial dysfunction. Finally, the highly irradiated fibrotic areas showed markers of reactive oxygen species such as decreased glutathione and increased lipid peroxides and a senescence-like phenotype. Conclusions: Based on our mouse model of RILD, we propose that irradiation-induced mitochondrial DNA instability contributes to the development of fibrosis via the generation of excessive reactive oxygen species, p53 pathway activation and a senescence-like phenotype. Lay summary: Irradiation is an efficient cancer therapy, however, its applicability to the liver is limited by life-threatening radiation-induced hepatic fibrosis. We have developed a new mouse model of radiation-induced liver fibrosis, that recapitulates the human disease. Our model highlights the role of mitochondrial DNA instability in the development of irradiation-induced liver fibrosis. This new model and subsequent findings will help increase our understanding of the hepatic reaction to irradiation and to find strategies that protect the liver, enabling the expanded use of radiotherapy to treat hepatic tumors.
