Translational Cancer Medicine Program, University of Helsinki, 00014 Helsinki, Finland
Emma W. Viitala
Translational Cancer Medicine Program, University of Helsinki, 00014 Helsinki, Finland
Linnea Wartiovaara
Translational Cancer Medicine Program, University of Helsinki, 00014 Helsinki, Finland
Pekka Päivinen
HiLIFE-Helsinki Institute of Life Science, University of Helsinki, 00014 Helsinki, Finland; iCAN Digital Precision Cancer Medicine Flagship, University of Helsinki, 00014 Helsinki, Finland
Heikki T. Virtanen
Department of Pharmacology, Faculty of Medicine, Helsinki Institute of Life Science, University of Helsinki, 00290 Helsinki, Finland
Nalle Pentinmikko
The Francis Crick Institute, London NW1 1AY, UK; Institute of Biotechnology, HiLIFE, University of Helsinki, 00014 Helsinki, Finland
Pekka Katajisto
Institute of Biotechnology, HiLIFE, University of Helsinki, 00014 Helsinki, Finland; Faculty of Biological and Environmental Sciences, Molecular and Integrative Biosciences Research Program, University of Helsinki, 00014 Helsinki, Finland; Department of Cell and Molecular Biology, Karolinska Institutet, 17177 Stockholm, Sweden
Tomi P. Mäkelä
HiLIFE-Helsinki Institute of Life Science, University of Helsinki, 00014 Helsinki, Finland; iCAN Digital Precision Cancer Medicine Flagship, University of Helsinki, 00014 Helsinki, Finland
Timothy C. Wang
Division of Digestive and Liver Diseases, Department of Medicine, Irving Cancer Research Center, Columbia University Medical Center, New York, NY 10032, USA
Jaan-Olle Andressoo
Department of Pharmacology, Faculty of Medicine, Helsinki Institute of Life Science, University of Helsinki, 00290 Helsinki, Finland; Division of Neurogeriatrics, Department of Neurobiology, Care Science and Society (NVS), Karolinska Institutet, 17177 Stockholm, Sweden
Saara Ollila
Translational Cancer Medicine Program, University of Helsinki, 00014 Helsinki, Finland; Faculty of Biological and Environmental Sciences, Molecular and Integrative Biosciences Research Program, University of Helsinki, 00014 Helsinki, Finland; Corresponding author
Summary: Enteroendocrine cells (EECs) differentiate and mature to form functionally distinct populations upon migration along the intestinal crypt-villus axis, but how niche signals affect this process is poorly understood. Here, we identify expression of Glial cell line-derived neurotrophic factor (GDNF) in the intestinal subepithelial myofibroblasts (SEMFs), while the GDNF receptor RET was expressed in a subset of EECs, suggesting GDNF-mediated regulation. Indeed, GDNF-RET signaling induced increased expression of EEC genes including Tph1, encoding for the rate-limiting enzyme for 5-hydroxytryptamine (5-HT, serotonin) biosynthesis, and increased the frequency of 5-HT+ enterochromaffin cells (ECs) in mouse organoid culture experiments and in vivo. Moreover, expression of the 5-HT receptor Htr4 was enriched in Lgr5+ intestinal stem cells (ISCs) and 5-HT reduced the ISC clonogenicity. In summary, our results show that GDNF-RET signaling regulate EEC differentiation, and suggest 5-HT as a potential niche factor regulating Lgr5+ ISC activity, with potential implications in intestinal regeneration.
