Myofibroblastic cells function as progenitors to regenerate murine livers after partial hepatectomy
Open accessAbstract
Objective: Smoothened (SMO), a coreceptor of the Hedgehog (Hh) pathway, promotes fibrogenic repair of chronic liver injury. We investigated the roles of SMO+ myofibroblast (MF) in liver regeneration by conditional deletion of SMO in α smooth muscle actin (αSMA)+ cells after partial hepatectomy (PH). Design: αSMA-Cre-ER T2 ×SMO/flox mice were treated with vehicle (VEH) or tamoxifen (TMX), and sacrificed 24–96 h post-PH. Regenerating livers were analysed for proliferation, progenitors and fibrosis by qRT-PCR and quantitative immunohistochemistry (IHC). Results were normalised to liver segments resected at PH. For lineage-tracing studies, αSMA-Cre-ER T2 ×ROSA-Stop-flox-yellow fluorescent protein (YFP) mice were treated with VEH or TMX; livers were stained for YFP, and hepatocytes isolated 48 and 72 h post-PH were analysed for YFP by flow cytometric analysis (FACS). Results: Post-PH, VEH-αSMA-SMO mice increased expression of Hh-genes, transiently accumulated MF, fibrosis and liver progenitors, and ultimately exhibited proliferation of hepatocytes and cholangiocytes. In contrast, TMX-αSMA-SMO mice showed loss of whole liver SMO expression, repression of Hh-genes, enhanced accumulation of quiescent HSC but reduced accumulation of MF, fibrosis and progenitors, as well as inhibition of hepatocyte and cholangiocyte proliferation, and reduced recovery of liver weight. In TMX-αSMA-YFP mice, many progenitors, cholangiocytes and up to 25% of hepatocytes were YFP+ by 48–72 h after PH, indicating that liver epithelial cells were derived from αSMA-YFP+ cells. Conclusions: Hh signalling promotes transition of quiescent hepatic stellate cells to fibrogenic MF, some of which become progenitors that regenerate the liver epithelial compartment after PH. Hence, scarring is a component of successful liver regeneration.
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Hedgehog ligands via their receptor Patched promote activation of HSCs in vitro and in mice, and show a positive correlation with progression from steatosis to steatohepatitis and myofibroblast activation in human livers.
“In addition to regulating liver regeneration, hedgehog ligands, via their receptor Patched, promote the activation of HSCs in vitro and in mice, and show a positive correlation with progression from steatosis to steatohepatitis and myofibroblast activation in human livers.39,40”
From Understanding the cellular interactome of non-alcoholic fatty liver disease (2022) · cites this paper as [39]
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- Authors
- Swiderska-Syn, M., Syn, W. K., Xie, G., Krüger, L., Machado, M. V., Karaca, G., Michelotti, G. A., Choi, S. S., Premont, R. T., & Diehl, A. M.
- Affiliations
- Division of Gastroenterology, Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA
- Foundation for Liver Research (GB)
- Duke Medical Center (US)
- Duke University (US)
- Corresponding author
- Diehl, A M
- Venue
- Gut
- Publisher
- BMJ
- Published
- 2013-10-30
- Volume
- 63
- Issue
- 8
- Pages
- 1333-1344
- ISSN
- 0017-5749 (ISSN-L)
- 1468-3288
- PMC
- PMC4006344
- OpenAlex
- W2114382572
- Cited by
- 115
- References
- 58
- Citations by year
- 2025: 6 · 2024: 4 · 2023: 2 · 2022: 9 · 2021: 12 · 2020: 11 · 2019: 5 · 2018: 8 · 2017: 9 · 2016: 16 · 2015: 12 · 2014: 18 · 2013: 3
- FWCI
- 10.15
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Gut (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- HighWire Press Open Archive (submittedVersion)
- Funders
- National Institutes of Health (5r37aa010154-20)
- National Institute on Alcohol Abuse and Alcoholism (R37 AA-010154)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK077794, T32DK007568)
- Topics
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Health Sciences › Medicine › Surgery › Tissue Engineering and Regenerative Medicine
- Health Sciences › Medicine › Surgery › Organ Transplantation Techniques and Outcomes
- Keywords
- myofibroblasts, liver regeneration, partial hepatectomy, Smoothened, Hedgehog signaling, hepatic stellate cells, liver fibrosis, progenitor cells, hepatocyte proliferation, cholangiocyte proliferation, alpha-smooth muscle actin, lineage tracing, conditional gene deletion
- MeSH terms
- Smoothened Receptor, Actins, Animals, Fibrosis, Hepatectomy, Immunohistochemistry, Liver Regeneration, Luminescent Proteins, Stem Cells, Tamoxifen, Signal Transduction, Gene Expression, Antineoplastic Agents, Hormonal, Hepatocytes, Receptors, G-Protein-Coupled, Mice, Hedgehog Proteins, Hepatic Stellate Cells, Myofibroblasts
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