Document Detail

In vitro expansion of single Lgr5+ liver stem cells induced by Wnt-driven regeneration.
MedLine Citation:
PMID:  23354049     Owner:  NLM     Status:  MEDLINE    
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.
Meritxell Huch; Craig Dorrell; Sylvia F Boj; Johan H van Es; Vivian S W Li; Marc van de Wetering; Toshiro Sato; Karien Hamer; Nobuo Sasaki; Milton J Finegold; Annelise Haft; Robert G Vries; Markus Grompe; Hans Clevers
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2013-01-27
Journal Detail:
Title:  Nature     Volume:  494     ISSN:  1476-4687     ISO Abbreviation:  Nature     Publication Date:  2013 Feb 
Date Detail:
Created Date:  2013-02-14     Completed Date:  2013-03-12     Revised Date:  2014-02-28    
Medline Journal Info:
Nlm Unique ID:  0410462     Medline TA:  Nature     Country:  England    
Other Details:
Languages:  eng     Pagination:  247-50     Citation Subset:  IM    
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MeSH Terms
Bile Ducts / cytology,  metabolism
Cell Lineage
Clone Cells / cytology,  metabolism
Culture Media / chemistry,  metabolism
Disease Models, Animal
Gene Knock-In Techniques
Hepatocytes / cytology*,  metabolism*,  pathology
Hydrolases / deficiency,  genetics
Liver / cytology,  metabolism,  pathology
Liver Diseases / metabolism,  pathology
Multipotent Stem Cells / cytology,  metabolism
Organoids / cytology,  transplantation
Receptors, G-Protein-Coupled / agonists,  deficiency,  genetics,  metabolism*
Stem Cells / cytology*,  metabolism*
Thrombospondins / deficiency,  genetics,  metabolism
Tyrosinemias / metabolism,  pathology
Wnt Signaling Pathway*
Grant Support
Reg. No./Substance:
0/Culture Media; 0/Lgr5 protein, mouse; 0/RSPO1 protein, mouse; 0/Receptors, G-Protein-Coupled; 0/Thrombospondins; EC 3.-/Hydrolases; EC
Comment In:
Hepatology. 2013 Nov;58(5):1847-50   [PMID:  23788312 ]

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