Autophagy-Related Activation of Hepatic Stellate Cells Reduces Cellular miR-29a by Promoting Its Vesicular SecretionSummary

Xiaojie Yu; Natalia Elfimova; Marion Müller; Daniel Bachurski; Ulrike Koitzsch; Uta Drebber; Esther Mahabir; Hinrich P. Hansen; Scott L. Friedman; Sabine Klein; Hans Peter Dienes; Marianna Hösel; Reinhard Buettner; Jonel Trebicka; Vangelis Kondylis; Inge Mannaerts; Margarete Odenthal

Cellular and Molecular Gastroenterology and Hepatology (Jan 2022)

Autophagy-Related Activation of Hepatic Stellate Cells Reduces Cellular miR-29a by Promoting Its Vesicular SecretionSummary

Xiaojie Yu,
Natalia Elfimova,
Marion Müller,
Daniel Bachurski,
Ulrike Koitzsch,
Uta Drebber,
Esther Mahabir,
Hinrich P. Hansen,
Scott L. Friedman,
Sabine Klein,
Hans Peter Dienes,
Marianna Hösel,
Reinhard Buettner,
Jonel Trebicka,
Vangelis Kondylis,
Inge Mannaerts,
Margarete Odenthal

Affiliations

Xiaojie Yu: Institute for Pathology, Medical Faculty and University Hospital of Cologne, University of Cologne, Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany
Natalia Elfimova: Institute for Pathology, Medical Faculty and University Hospital of Cologne, University of Cologne, Cologne, Germany
Marion Müller: Institute for Pathology, Medical Faculty and University Hospital of Cologne, University of Cologne, Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany
Daniel Bachurski: Department I of Internal Medicine, Medical Faculty and University Hospital of Cologne, University of Cologne, Cologne, Germany
Ulrike Koitzsch: Institute for Pathology, Medical Faculty and University Hospital of Cologne, University of Cologne, Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany
Uta Drebber: Institute for Pathology, Medical Faculty and University Hospital of Cologne, University of Cologne, Cologne, Germany; Center of Integrative Oncology, University Clinic of Cologne and Bonn, Germany
Esther Mahabir: Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany
Hinrich P. Hansen: Department I of Internal Medicine, Medical Faculty and University Hospital of Cologne, University of Cologne, Cologne, Germany; Center of Integrative Oncology, University Clinic of Cologne and Bonn, Germany
Scott L. Friedman: Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York
Sabine Klein: Department of Internal Medicine I, University Hospital Frankfurt, Frankfurt, Germany
Hans Peter Dienes: Institute for Pathology, Medical Faculty and University Hospital of Cologne, University of Cologne, Cologne, Germany
Marianna Hösel: Institute for Pathology, Medical Faculty and University Hospital of Cologne, University of Cologne, Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany
Reinhard Buettner: Institute for Pathology, Medical Faculty and University Hospital of Cologne, University of Cologne, Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany; Center of Integrative Oncology, University Clinic of Cologne and Bonn, Germany
Jonel Trebicka: Department of Internal Medicine I, University Hospital Frankfurt, Frankfurt, Germany; European Foundation for the Study of Chronic Liver Failure - EF CLIF, Barcelona, Spain
Vangelis Kondylis: Institute for Pathology, Medical Faculty and University Hospital of Cologne, University of Cologne, Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany
Inge Mannaerts: Liver Cell Biology Research Group, Vrije Universiteit Brussel, Brussel, Belgium; Correspondence Address correspondence to: Inge Mannaerts, PhD, Vrije Universiteit Brussel, Brussel, Belgium.
Margarete Odenthal: Institute for Pathology, Medical Faculty and University Hospital of Cologne, University of Cologne, Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany; Center of Integrative Oncology, University Clinic of Cologne and Bonn, Germany; Margarete Odenthal, PhD, Institute for Pathology, University Hospital Cologne, Kerpener Str. 62, 50937 Cologne, Germany. fax: +49-221-478-6360.

Journal volume & issue: Vol. 13, no. 6
pp. 1701 – 1716

Abstract

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Background & Aims: Liver fibrosis arises from long-term chronic liver injury, accompanied by an accelerated wound healing response with interstitial accumulation of extracellular matrix (ECM). Activated hepatic stellate cells (HSC) are the main source for ECM production. MicroRNA29a (miR-29a) is a crucial antifibrotic miRNA that is repressed during fibrosis, resulting in up-regulation of collagen synthesis. Methods: Intracellular and extracellular miRNA levels of primary and immortalized myofibroblastic HSC in response to profibrogenic stimulation by transforming growth factor β (TGFβ) or platelet-derived growth factor-BB (PDGF-BB) or upon inhibition of vesicular transport and autophagy processes were determined by quantitative polymerase chain reaction. Autophagy flux was studied by electron microscopy, flow cytometry, immunoblotting, and immunocytochemistry. Hepatic and serum miR-29a levels were quantified by using both liver tissue and serum samples from a cohort of chronic hepatitis C virus patients and a murine CCl4 induced liver fibrosis model. Results: In our study, we show that TGFβ and PDGF-BB resulted in decrease of intracellular miR-29a and a pronounced increase of vesicular miR-29a release into the supernatant. Strikingly, miR-29a vesicular release was accompanied by enhanced autophagic activity and up-regulation of the autophagy marker protein LC3. Moreover, autophagy inhibition strongly prevented miR-29a secretion and repressed its targets’ expression such as Col1A1. Consistently, hepatic miR-29a loss and increased LC3 expression in myofibroblastic HSC were associated with increased serum miR-29a levels in CCl4-treated murine liver fibrosis and specimens of hepatitis C virus patients with chronic liver disease. Conclusions: We provide evidence that activation-associated autophagy in HSC induces release of miR-29a, whereas inhibition of autophagy represses fibrogenic gene expression in part through attenuated miR-29a secretion.

Published in Cellular and Molecular Gastroenterology and Hepatology

ISSN: 2352-345X (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Medicine: Internal medicine: Specialties of internal medicine: Diseases of the digestive system. Gastroenterology
Website: https://www.journals.elsevier.com/cellular-and-molecular-gastroenterology-and-hepatology/

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