Unlimited in vitro expansion of adult bi-potent pancreas progenitors through the Lgr5/R-spondin axis

Meritxell Huch, Paola Bonfanti, Sylvia F. Boj, Toshiro Sato, Cindy J.M. Loomans, Marc Van De Wetering, Mozhdeh Sojoodi, Vivian S.W. Li, Jurian Schuijers, Ana Gracanin, Femke Ringnalda, Harry Begthel, Karien Hamer, Joyce Mulder, Johan H. Van Es, Eelco De Koning, Robert G.J. Vries, Harry Heimberg, Hans Clevers

Research output: Contribution to journalArticlepeer-review

318 Citations (Scopus)

Abstract

Lgr5 marks adult stem cells in multiple adult organs and is a receptor for the Wnt-agonistic R-spondins (RSPOs). Intestinal, stomach and liver Lgr5 + stem cells grow in 3D cultures to form ever-expanding organoids, which resemble the tissues of origin. Wnt signalling is inactive and Lgr5 is not expressed under physiological conditions in the adult pancreas. However, we now report that the Wnt pathway is robustly activated upon injury by partial duct ligation (PDL), concomitant with the appearance of Lgr5 expression in regenerating pancreatic ducts. In vitro, duct fragments from mouse pancreas initiate Lgr5 expression in RSPO1-based cultures, and develop into budding cyst-like structures (organoids) that expand five-fold weekly for >40 weeks. Single isolated duct cells can also be cultured into pancreatic organoids, containing Lgr5 stem/progenitor cells that can be clonally expanded. Clonal pancreas organoids can be induced to differentiate into duct as well as endocrine cells upon transplantation, thus proving their bi-potentiality.

Original languageEnglish
Pages (from-to)2708-2721
Number of pages14
JournalEMBO Journal
Volume32
Issue number20
DOIs
Publication statusPublished - 2013 Oct 16

Keywords

  • Wnt
  • beta cell
  • duct cell
  • pancreas
  • stem cell

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

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