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- Title
In vitro expansion of single Lgr5<sup>+</sup> liver stem cells induced by Wnt-driven regeneration.
- Authors
Huch, Meritxell; Dorrell, Craig; Boj, Sylvia F.; van Es, Johan H.; Li, Vivian S. W.; van de Wetering, Marc; Sato, Toshiro; Hamer, Karien; Sasaki, Nobuo; Finegold, Milton J.; Haft, Annelise; Vries, Robert G.; Grompe, Markus; Clevers, Hans
- Abstract
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.
- Subjects
STEM cells; LIVER; WNT genes; REGENERATION (Biology); G proteins
- Publication
Nature, 2013, Vol 494, Issue 7436, p247
- ISSN
0028-0836
- Publication type
Article
- DOI
10.1038/nature11826