Fate-tracing reveals hepatic stellate cells as dominant contributors to liver fibrosis independent of its etiology

By I. Mederacke, Christine C. Hsu, Juliane S. Troeger, P. Huebener, Xueru Mu, D. Dapito, J. Pradère, Robert F. Schwabe. Nature Communications, 2013

1,315 citations recorded by the source corpus.

Although organ fibrosis causes significant morbidity and mortality in chronic diseases, the lack of detailed knowledge about specific cellular contributors mediating fibrogenesis hampers the design of effective antifibrotic therapies. Different cellular sources, including tissue-resident and bone marrow-derived fibroblasts, pericytes and epithelial cells, have been suggested to give rise to myofibroblasts, but their relative contributions remain controversial, with profound differences between organs and different diseases. Here we employ a novel Cre-transgenic mouse that marks 99% of hepatic stellate cells (HSCs), a liver-specific pericyte population, to demonstrate that HSCs give rise to 82–96% of myofibroblasts in models of toxic, cholestatic and fatty liver disease. Moreover, we exclude that HSCs function as facultative epithelial progenitor cells in the injured liver. On the basis these findings, HSCs should be considered the primary cellular target for antifibrotic therapies across all types of liver disease. Myofibroblasts drive fibrogenesis in the liver but their cellular origins remain unclear. Here Mederacke et al. use the Lratgene to label hepatic stellate cells (HSCs) in transgenic mice and reveal HSCs as the major source of myofibroblasts in models of toxic, biliary and fatty liver fibrosis.

Subfields: Epidemiology, Genetics, Hepatology

View Paper: https://www.semanticscholar.org/paper/c1670d7e0534ed2a4ebca3691c62d281f7081235

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Epidemiology

1. M. Pinzani
2. E. Seki
3. Robert F. Schwabe
4. M. Parola
5. Natascha Roehlen
6. E. Crouchet
7. T. Baumert
8. S. Friedman

In Genetics

1. M. Pinzani
2. Robert F. Schwabe
3. Natascha Roehlen
4. E. Seki
5. M. Parola
6. E. Crouchet
7. T. Baumert

In Hepatology

1. E. Seki
2. M. Pinzani
3. M. Parola
4. Natascha Roehlen
5. E. Crouchet
6. T. Baumert
7. Robert F. Schwabe
8. Le-xing Yu

Citations in the corpus

• Liver fibrosis: Pathophysiology, pathogenetic targets and clinical issues. (2019, background): “several negative fate tracing murine studies (Taura et al., 2010; Scholten et al., 2010; Chu et al., 2011; Österreicher et al., 2011; Mederacke et al., 2013; Iwaisako et al., 2014).”
• Liver Fibrosis: Mechanistic Concepts and Therapeutic Perspectives (2020, background): “HSCs are the main myofibroblast progenitor cells and therefore key effectors of the fibrogenic response [51].”
• Primary sclerosing cholangitis - a comprehensive review. (2017, background): “Although details are not clear, this activation is likely important for the peribiliary fibrosis development and subsequent cirrhosis, by interactions with hepatic stellate cells (114), portal myofibroblasts (115), or both.”
• Hepatic inflammatory responses in liver fibrosis (2023, neutral): “HSCs are the main effector cells during hepatic fibrogenesis 12 .”
• Hepatic Inflammation and Fibrosis: Functional Links and Key Pathways (2015, background): “Recent fatetracing studies in multiple models of murine cholestatic liver fibrosis demonstrated that HSCs—and not portal fibroblasts—are the main ECM-producing cell type.(1) However, the interactions between cholangiocytes and HSCs are not well characterized, and it is not known whether chemokines o”
• The Role of Cancer-Associated Fibroblasts and Fibrosis in Liver Cancer (2016, background): “Although recent studies in multiple models of liver injury have highlighted the dominant role of HSCs as a source of hepatic myofibroblasts (44), the cellular source of myofibroblasts in the TME remains elusive.”