Z Gastroenterol 2020; 58(01): e9-e10
DOI: 10.1055/s-0039-3402123
Poster Visit Session I Basic Hepatology (Fibrogenesis, NPC, Transport): Friday, February 14, 2020, 12:30 pm – 1:15 pm, Lecture Hall P1
Georg Thieme Verlag KG Stuttgart · New York

Fibrocytes contribute to TAA-induced liver fibrosis in mice

F Hempel
1   Justus Liebig University, Department of Gastroenterology, Gießen, Germany
,
M Roderfeld
1   Justus Liebig University, Department of Gastroenterology, Gießen, Germany
,
R Savai
2   Max Planck Institute for Heart and Lung Research, Member of the German Center for Lung Research (DZL), Member of the Cardio-Pulmonary Institute (CPI), Bad Nauheim, Germany
3   Justus Liebig University, Department of Internal Medicine, Cardio-Pulmonary Institute (CPI), Universities of Gießen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Gießen, Germany
,
A Sydykov
3   Justus Liebig University, Department of Internal Medicine, Cardio-Pulmonary Institute (CPI), Universities of Gießen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Gießen, Germany
,
K Irungbam
1   Justus Liebig University, Department of Gastroenterology, Gießen, Germany
,
R Schermuly
3   Justus Liebig University, Department of Internal Medicine, Cardio-Pulmonary Institute (CPI), Universities of Gießen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Gießen, Germany
,
R Voswinckel
4   Bürgerhospital, Friedberg, Germany
5   Hochwaldkrankenhaus, Bad Nauheim, Germany
,
K Köhler
6   Justus Liebig University, Institute of Veterinary Pathology, Gießen, Germany
,
Y Churin
1   Justus Liebig University, Department of Gastroenterology, Gießen, Germany
,
L Kiss
3   Justus Liebig University, Department of Internal Medicine, Cardio-Pulmonary Institute (CPI), Universities of Gießen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Gießen, Germany
,
J Bier
3   Justus Liebig University, Department of Internal Medicine, Cardio-Pulmonary Institute (CPI), Universities of Gießen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Gießen, Germany
,
J Pons-Kühnemann
7   Justus Liebig University, Institute of Medical Informatics, Gießen, Germany
,
E Roeb
1   Justus Liebig University, Department of Gastroenterology, Gießen, Germany
› Author Affiliations
Further Information

Publication History

Publication Date:
03 January 2020 (online)

Also available at
 

Background:

Bone marrow-derived fibrocytes represent a unique cell type, sharing features of both mesenchymal and hematopoietic cells. They comprise ˜0.5% of peripheral blood leucocytes and have been implicated in fibrotic diseases of the kidney, lung, heart, and liver. Fibrocytes were shown to specifically infiltrate the injured liver and participate in the deposition of extracellular matrix components. Moreover, fibrocytes hold the potential to regulate fibrogenesis via the secretion of TGF-β, MMPs, TNF-α, IL-1β, and other inflammatory cytokines. Their relevance to hepatic fibrosis, however, remains unknown. We aimed to study the effect of a fibrocyte depletion during fibrogenesis in a mouse model of chronic-toxic liver fibrosis.

Methods:

Fibrocytes were depleted utilizing a suicide gene strategy. Bone marrow of transgene C57BL/6J mice, expressing a herpes simplex virus thymidine kinase (HSV-TK) under the control of a collagen I promotor, was transplanted into lethally irradiated mice of the same genetic background (n = 16 per group, mice of the control group received wild-type bone marrow). Thioacetamide (TAA) and Valganciclovir, which is metabolized into toxic compounds by the HSV-TK, were administered via drinking water for 18 weeks to induce fibrosis and specifically deplete bone marrow-derived fibrocytes.

Results:

TAA-administration induced a marked perilobular fibrosis. RNA in situ hybridization visualized fibrocytes in liver samples of the control group and proved the suicide gene strategy's success. The depletion of fibrocytes lead to a significantly reduced amount of fibrillar collagens, indicated by decreased hepatic hydroxyproline content (-7.8%; 95% CI: 0.7 – 14.8%; p= 0.033). The expression and distribution of α-SMA was unchanged in western blot, immunohistochemistry, and RT-qPCR in result of the fibrocyte ablation. High-throughput analyses of a panel of MMPs and inflammatory mediators yielded no relevant regulations. Yet lower serum ALT levels (-20.9%; 95% CI: 0.4 – 36.9%; p= 0.049) show a mitigation of liver-specific cellular damage.

Conclusion:

Our model enabled the study of fibrocytes in a complex in vivo setting. Fibrocytes functionally contribute to TAA-induced liver fibrosis, as our results suggest, independent of the activation or proliferation of myofibroblasts.