Unlimited in vitro expansion of adult bi‐potent pancreas progenitors through the Lgr5/R‐spondin axis |
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| Authors: | Meritxell Huch Paola Bonfanti Sylvia F Boj Cindy J M Loomans Marc van de Wetering Mozhdeh Sojoodi 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 |
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| Institution: | 1. Hubrecht Institute for Developmental Biology and Stem Cell Research, University Medical Centre Utrecht, , Utrecht, The Netherlands;2. Diabetes Research Center, Vrije Universiteit Brussel, , Brussels, Belgium;3. Department of Nephrology, Leiden University Medical Center, Albinusdreef 2, , Leiden, The Netherlands |
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| 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. |
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| Keywords: | beta cell duct cell pancreas Wnt stem cell |
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