In vitro expansion of single Lgr5+ liver stem cells induced by Wnt-driven regeneration
Open accessAbstract
The Wnt target gene Lgr5 (leucine-rich-repeat-containing G-protein-coupled receptor 5) marks actively dividing stem cells in Wnt-driven, self-renewing tissues such as small intestine and colon, stomach and hair follicles. A three-dimensional culture system allows long-term clonal expansion of single Lgr5(+) stem cells into transplantable organoids (budding cysts) that retain many characteristics of the original epithelial architecture. A crucial component of the culture medium is the Wnt agonist RSPO1, the recently discovered ligand of LGR5. Here we show that Lgr5-lacZ is not expressed in healthy adult liver, however, small Lgr5-LacZ(+) cells appear near bile ducts upon damage, coinciding with robust activation of Wnt signalling. As shown by mouse lineage tracing using a new Lgr5-IRES-creERT2 knock-in allele, damage-induced Lgr5(+) cells generate hepatocytes and bile ducts in vivo. Single Lgr5(+) cells from damaged mouse liver can be clonally expanded as organoids in Rspo1-based culture medium over several months. Such clonal organoids can be induced to differentiate in vitro and to generate functional hepatocytes upon transplantation into Fah(-/-) mice. These findings indicate that previous observations concerning Lgr5(+) stem cells in actively self-renewing tissues can also be extended to damage-induced stem cells in a tissue with a low rate of spontaneous proliferation.
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Liver organoids derived from LGR5-positive liver progenitor cells can be stably maintained for months and can differentiate into functionally competent hepatocytes and cholangiocytes.
“Liver organoids derived from leucine-rich repeat–containing G protein–coupled receptor 5 (LGR5)–positive liver progenitor cells (LPC) can be stably maintained for months and can differentiate into functionally competent hepatocytes and cholangiocytes [14–16].”
From High-throughput human microfluidic organoid-on-a-chip platform for modeling liver diseases and screening nanotherapeutics. (2026) · cites this paper as [14]
The paper reports that organoids grown from single Lgr5-positive liver cells were maintained for more than eight months, and that differentiated organoids performed hepatocyte functions including LDL uptake and albumin secretion (Abstract; page not provided). It also reports bile-duct markers and a retained ductal phenotype, but does not establish that the organoids differentiated into functionally competent cholangiocytes. (LLM, conf=0.87)
Experimental — accuracy not yet measuredThe liver organoid has self-renewal capability, a key proliferative property for its long-term culture and clonal expansion from single cells with sustained stemness.
“The liver organoid has selfrenewal capability, a key proliferative property for its long-term culture and clonal expansion from single cells with sustained stemness (Huch et al., 2013;Hu et al., 2018).”
From Fast formation and maturation enhancement of human liver organoids using a liver-organoid-on-a-chip (2024) · cites this paper as Huch et al., 2013
Recent studies have demonstrated that HPCs arise within the liver, engraft the parenchyma, and may have some differentiation capacity but did not regenerate significant quantities of liver parenchyma.
“These studies demonstrated that HPCs arise within the liver, engraft the parenchyma14 and may have some differentiation capacity but did not regenerate significant quantities of liver parenchyma11-13.”
From Hepatic progenitor cells of biliary origin with liver repopulation capacity (2015) · cites this paper as [12]
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- Authors
- Huch, M., Dorrell, C., Boj, S. F., van Es, J. H., Li, V. S. W., van de Wetering, M., Sato, T., Hamer, K., Sasaki, N., Finegold, M. J., Haft, A., Vries, R. G., Grompe, M., & Clevers, H.
- Affiliations
- Utrecht University (NL)
- Oregon Health & Science University (US)
- Keio University (JP)
- Baylor College of Medicine (US)
- Corresponding author
- Clevers, Hans
- ORCID
- Venue
- Nature
- Published
- 2013-01-27
- Volume
- 494
- Issue
- 7436
- Pages
- 247-250
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC3634804
- OpenAlex
- W2008285918
- Cited by
- 1,555
- References
- 31
- Citations by year
- 2026: 66 · 2025: 117 · 2024: 148 · 2023: 118 · 2022: 122 · 2021: 143 · 2020: 146 · 2019: 120 · 2018: 125 · 2017: 120 · 2016: 109 · 2015: 80 · 2014: 95 · 2013: 43 · 2012: 1
- FWCI
- 67.87
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- KNAW Research Portal (The Royal Netherlands Academy of Arts and Sciences) (submittedVersion)
- Funders
- Wellcome Trust (104151)
- Japan Society for the Promotion of Science
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK051592, P30DK056338)
- Topics
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
- Health Sciences › Medicine › Surgery › Tissue Engineering and Regenerative Medicine
- Keywords
- Wnt signaling, liver regeneration, liver organoids, hepatocyte differentiation, bile duct regeneration, tyrosinemia type I, RSPO1, clonal expansion, stem cell transplantation, liver injury, lineage tracing
- MeSH terms
- Alleles, Animals, Bile Ducts, Clone Cells, Culture Media, Disease Models, Animal, Female, Hydrolases, Liver, Liver Diseases, Male, Organoids, Regeneration, Stem Cells, Cell Lineage, Thrombospondins, Tyrosinemias, Hepatocytes, Multipotent Stem Cells, Receptors, G-Protein-Coupled, Mice, Gene Knock-In Techniques, Wnt Signaling Pathway
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