Fibroblasts Derive from Hepatocytes in Liver Fibrosis via Epithelial to Mesenchymal Transition*

By M. Zeisberg, Changqing Yang, M. Martino, Michael B. Duncan, F. Rieder, H. Tanjore, Raghu Kalluri. Journal of Biological Chemistry, 2007

846 citations recorded by the source corpus.

Activated fibroblasts are key contributors to the fibrotic extracellular matrix accumulation during liver fibrosis. The origin of such fibroblasts is still debated, although several studies point to stellate cells as the principal source. The role of adult hepatocytes as contributors to the accumulation of fibroblasts in the fibrotic liver is yet undetermined. Here, we provide evidence that the pro-fibrotic growth factor, TGF-β1, induces adult mouse hepatocytes to undergo phenotypic and functional changes typical of epithelial to mesenchymal transition (EMT). We perform lineage-tracing experiments using AlbCre. R26RstoplacZ double transgenic mice to demonstrate that hepatocytes which undergo EMT contribute substantially to the population of FSP1-positive fibroblasts in CCL4-induced liver fibrosis. Furthermore, we demonstrate that bone morphogenic protein-7 (BMP7), a member of the TGFβ superfamily, which is known to antagonize TGFβ signaling, significantly inhibits progression of liver fibrosis in these mice. BMP7 treatment abolishes EMT-derived fibroblasts, suggesting that the therapeutic effect of BMP7 was at least partially due to the inhibition of EMT. These results provide direct evidence for the functional involvement of adult hepatocytes in the accumulation of activated fibroblasts in the fibrotic liver. Furthermore, our findings suggest that EMT is a promising therapeutic target for the attenuation of liver fibrosis.

Subfields: Epidemiology, Hepatology, Surgery

View Paper: https://www.semanticscholar.org/paper/b20770c43b2ecf6cd27ef8a3275bee50c78d5264

How researchers see this paper

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In Epidemiology

1. Natascha Roehlen
2. E. Crouchet
3. T. Baumert
4. M. Nieto
5. J. P. Thiery
6. S. Friedman
7. Y. Saiman
8. J. Puche

In Hepatology

1. T. Baumert
2. Natascha Roehlen
3. E. Crouchet
4. M. Nieto
5. S. Friedman
6. Y. Saiman
7. J. Puche
8. J. Bonner

In Surgery

1. J. López-Novoa
2. M. Nieto
3. J. P. Thiery
4. S. Friedman
5. H. Acloque

Citations in the corpus

• Therapy for Fibrotic Diseases: Nearing the Starting Line (2013, background): “The use of anti-inflammatory drugs in suppressing or reversing fibrosis Cell death Pathologic EMT TGFβ activation Immune responses Inflammation Toxins Cell stress ER stress ROS Innate lymphoid cells Extracellular matrix Myofibroblasts T cells Macrophages Infection (viruses and bacteria)Trauma Pro-fi”
• The ins and outs of the epithelial to mesenchymal transition in health and disease. (2011, background): “…of these intermediate states has also been described in renal or liver epithelial cells during the course of fibrosis (Iwano et al. 2002, Zeisberg et al. 2007b) and also halfway during the transition from endothelium to mesenchyme (EndMT) in renal and cardiac fibrosis (Zeisberg et al. 2007a, 2008).”
• Epithelial-mesenchymal transitions in development and disease. (2009, background): “EMT involving transformation of endothelial cells into mesenchymal cells is evident during cardiac and renal fibrosis (EndMT) (Zeisberg et al., 2007a, 2008).”
• Fibrosis and adipogenesis originate from a common mesenchymal progenitor in skeletal muscle (2011, background): “In addition, Zeisberg et al. reported that adult hepatocytes contribute to liver fibrosis by means of an epithelial–mesenchymal transition (EMT) (Zeisberg et al., 2007b).”
• Liver Fibrosis: Mechanistic Concepts and Therapeutic Perspectives (2020, background): “EMT is a reversible process by which epithelial cells lose their polarity and can differentiate into mesenchymal cells.”
• Evolving challenges in hepatic fibrosis (2010, background): “In liver studies, experimental models have identified both hepatocyte”
• Epithelial cell cycle arrest in G2/M mediates kidney fibrosis after injury (2010, neutral): “TGF-β1 is a well-established principal driver of fibrosis via promotion of fibroblast proliferation, extracellular matrix synthesis and inhibition of collagenases in multiple organ”
• Epithelial Plasticity: A Common Theme in Embryonic and Cancer Cells (2013, background): “the progression of organ fibrosis, when parenchymal (epithelial) cells have activated the EMT program and show both epithelial and mesenchymal markers (31).”
• Inflammation and EMT: an alliance towards organ fibrosis and cancer progression (2009, background): “A similar process also occurs when endothelial cells undergo an EMT during cardiac or renal fibrosis (EndMT; Zeisberg et al, 2007b, 2008) as well as during mesothelial fibrosis in patients subjected to peritoneal dialysis where the NF-kB/Snail1 axis has already been described (Strippoli et al,…”