The DOI matches its Crossref record; 56 of the 56 references it cites were found in a registry or an index.
Fate tracing reveals hepatic stellate cells as dominant contributors to liver fibrosis independent of its aetiology
Open accessAbstract
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.
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“Besides HSCs, other cells, including portal fibroblasts (particularly in cholestatic liver fibrosis), bone marrow-derived fibrocytes, and MSCs contribute to the pool of MFs as well, albeit to a minor extent [7, 13].”
From Mechanisms, efficacy, and future perspectives of cellular-based therapies for liver fibrosis/cirrhosis: focusing on mesenchymal stromal cells (2025) · cites this paper as [13]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“hepatic stellate cells, the predominant (>95%) source of collagen-producing cells and myofibroblasts in liver fibrosis 15,43 .”
From Amphiregulin from regulatory T cells promotes liver fibrosis and insulin resistance in non-alcoholic steatohepatitis (2024) · cites this paper as [15]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“In the fibrotic liver, activated HSCs (aHSCs) have been identified as the predominant source (> 80%) of MFs [7, 13].”
From Mechanisms, efficacy, and future perspectives of cellular-based therapies for liver fibrosis/cirrhosis: focusing on mesenchymal stromal cells (2025) · cites this paper as [13]
The cited source says what the claim attributes to it.
In the citing paper
“Hepatic stellate cells - liver-resident fibroblasts - are central to liver fibrosis 15 and interplay with hepatocytes via cell-cell contact and soluble mediators that support hepatocyte development and homeostasis 16,17 .”
From Amphiregulin from regulatory T cells promotes liver fibrosis and insulin resistance in non-alcoholic steatohepatitis (2024) · cites this paper as [15]
In the citing paper
“Following injury, HSCs undergo a well-characterized activation process and become the primary fibrogenic cell type of the liver [221, 227, 228].”
From Inflammation and immunity in liver homeostasis and disease: a nexus of hepatocytes, nonparenchymal cells and immune cells (2025) · cites this paper as [227]
In the citing paper
“Fibrogenesis is driven by myofibroblasts, originating mainly from hepatic stellate cells (HSCs) and portal fibroblasts (3, 4) that acquire fibrogenic, proliferative, immunomodulatory, contractile, and angiogenic properties in response to liver injury (1, 5).”
From Immunoregulation of Liver Fibrosis: New Opportunities for Antifibrotic Therapy (2024) · cites this paper as [4]
In the citing paper
“In rodent models of parenchymal injury, it is predominantly HSCs that activate and differentiate into myofibroblasts.112,113”
From Understanding the cellular interactome of non-alcoholic fatty liver disease (2022) · cites this paper as [113]
In the citing paper
“The majority of myofibroblasts in chemically-injured mouse models also derive from HSCs, and their depletion reduces liver fibrosis (52-54).”
From Found in translation—Fibrosis in metabolic dysfunction–associated steatohepatitis (MASH) (2023) · cites this paper as [53]
In the citing paper
“Other sources of myofibroblasts include vascular smooth muscle cells, mesothelial cells, and portal fibroblasts, out of which portal myofibroblasts marked by thymocyte differentiation antigen 1 (THY1) may play an outsized role in biliary fibrosis due to their physical localization in the portal region (53, 55-57) (58).”
From Found in translation—Fibrosis in metabolic dysfunction–associated steatohepatitis (MASH) (2023) · cites this paper as [53]
In the citing paper
“The primary cellular driver of liver fibrogenesis is activated hepatic stellate cells.”
From Nuclear receptors in liver fibrosis (2021) · cites this paper as [6]
In the citing paper
“While aHSCs represent the main source of fibrogenic MFs, [6]”
From Nuclear receptors in liver fibrosis (2021) · cites this paper as [6]
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Citations
Cites
A robust and high-throughput Cre reporting and characterization system for the whole mouse brain
Madisen, L., Zwingman, T. A., Sunkin, S. M., Oh, S. W., Zariwala, H. A., Gu, H., Ng, L. L., Palmiter, R. D., Hawrylycz, M. J., Jones, A. R., et al. (2010) · Nature Neuroscience · doi:10.1038/nn.2467 · Cited by 6,907
Bataller, R., & Brenner, D. A. (2005) · Journal of Clinical Investigation · doi:10.1172/jci24282 · Cited by 4,958
Mechanisms of fibrosis: therapeutic translation for fibrotic disease
Wynn, T. A., & Ramalingam, T. R. (2012) · Nature Medicine · doi:10.1038/nm.2807 · Cited by 3,541
A global double-fluorescent Cre reporter mouse
Muzumdar, M. D., Tasic, B., Miyamichi, K., Li, L., & Luo, L. (2007) · genesis · doi:10.1002/dvg.20335 · Cited by 3,491
Hepatic Stellate Cells: Protean, Multifunctional, and Enigmatic Cells of the Liver
Friedman, S. L. (2008) · Physiological Reviews · doi:10.1152/physrev.00013.2007 · Cited by 2,842
Mechanisms of Hepatic Fibrogenesis
Friedman, S. L. (2008) · Gastroenterology · doi:10.1053/j.gastro.2008.03.003 · Cited by 2,687
Pericytes: Developmental, Physiological, and Pathological Perspectives, Problems, and Promises
Armulik, A., Genové, G., & Betsholtz, C. (2011) · Developmental Cell · doi:10.1016/j.devcel.2011.07.001 · Cited by 2,653
TLR4 enhances TGF-β signaling and hepatic fibrosis
Seki, E., De Minicis, S., Österreicher, C. H., Kluwe, J., Osawa, Y., Brenner, D. A., & Schwabe, R. F. (2007) · Nature Medicine · doi:10.1038/nm1663 · Cited by 1,942
Self-citationThe myofibroblast in wound healing and fibrocontractive diseases
Gabbiani, G. (2003) · The Journal of Pathology · doi:10.1002/path.1427 · Cited by 1,630
Bataller, R. A. (2005) · Journal of Clinical Investigation · doi:10.1172/jci200524282c1 · Cited by 1,480
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Pan, X., Gao, T., & Wang, B. (2025) · Cell & Bioscience · doi:10.1186/s13578-025-01520-9 · Cited by 2
“%) of MFs [7, 13].”
Metadata
- Authors
- Mederacke, I., Hsu, C. C., Troeger, J. S., Huebener, P., Mu, X., Dapito, D. H., Pradere, J.-P., & Schwabe, R. F.
- Affiliations
- Columbia University (US)
- Corresponding author
- Schwabe, Robert F.
- Venue
- Nature Communications
- Published
- 2013-11-22
- Volume
- 4
- Issue
- 1
- Pages
- 2823-2823
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC4059406
- OpenAlex
- W1965588383
- Cited by
- 1,443
- References
- 56
- Citations by year
- 2026: 111 · 2025: 126 · 2024: 121 · 2023: 194 · 2022: 136 · 2021: 116 · 2020: 124 · 2019: 101 · 2018: 97 · 2017: 91 · 2016: 80 · 2015: 85 · 2014: 53 · 2013: 3
- FWCI
- 45.87
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Nature Communications (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- American Liver Foundation (ME 3723/1-1, 1F31DK091980)
- Case Western Reserve University
- Deutsche Forschungsgemeinschaft (1F31DK091980, ME 3723/1-1)
- National Institutes of Health
- University of California, San Diego
- National Cancer Institute (U54CA163111)
- National Institute of Diabetes and Digestive and Kidney Diseases (5R01DK76920, R01DK076920, F31DK091980, R01DK075830)
- Topics
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Health Sciences › Medicine › Hepatology › Liver Disease Diagnosis and Treatment
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
- Keywords
- hepatic stellate cells, liver fibrosis, myofibroblast origin, fibrogenesis, toxic liver injury, cholestatic liver disease, hepatic steatosis, antifibrotic therapy, bone marrow-derived fibroblasts, pericytes, epithelial progenitor cells
- MeSH terms
- Animals, Female, Liver Cirrhosis, Male, Mice, Inbred CBA, Mice, Inbred C57BL, Genes, Reporter, Integrases, Mice, Hepatic Stellate Cells, Myofibroblasts
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