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Unlimited in vitro expansion of adult bi‐potent pancreas progenitors through the Lgr5/R‐spondin axis
Author(s) -
Huch Meritxell,
Bonfanti Paola,
Boj Sylvia F,
Sato Toshiro,
Loomans Cindy J M,
van de Wetering Marc,
Sojoodi Mozhdeh,
Li Vivian S W,
Schuijers Jurian,
Gracanin Ana,
Ringnalda Femke,
Begthel Harry,
Hamer Karien,
Mulder Joyce,
van Es Johan H,
de Koning Eelco,
Vries Robert G J,
Heimberg Harry,
Clevers Hans
Publication year - 2013
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1038/emboj.2013.204
Subject(s) - lgr5 , biology , organoid , stem cell , wnt signaling pathway , pancreas , microbiology and biotechnology , progenitor cell , transplantation , medicine , endocrinology , cancer stem cell , signal transduction
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.