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Here, we investigated the roles of gastrin (GAST), cholecystokinin (CCK) and their receptor cholecystokinin B receptor (CCKBR) during human pancreatic development.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Human iPSCs were differentiated stepwise into definitive endoderm and then the pancreatic endocrine lineage. To assess CCKBR function, CRISPR\/Cas9 was used to generate CCKBR-knockout iPSC lines. We profiled transcriptional states by bulk and single-cell RNA-seq with computational analyses, and complemented these with biochemical assays, flow cytometry (FACS) and confocal microscopy.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      <jats:italic>CCKBR<\/jats:italic>\n                      expression peaked during definitive endoderm formation and progressively declined during differentiation, remaining detectable in pancreatic progenitors but largely absent from the endocrine lineage. By contrast, GAST and CCK were expressed only transiently during pancreatic progenitor and endocrine lineage formation. Pharmacological activation\/inhibition and genetic knockout implicated CCKBR signalling during definitive endoderm formation. Consistently, bulk RNA-seq indicated that CCKBR deletion triggered ectodermal- and mesodermal-associated transcriptional programs and diminished pancreatic lineage specification. During pancreatic induction and lineage formation, sustained CCKBR activation with GAST or CCK attenuated endocrinogenesis and promoted epithelial structure formation. Further analysis revealed the emergence of a pancreatic ductal-like cell formation under prolonged CCKBR stimulation.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions\/interpretation<\/jats:title>\n                    <jats:p>This study provides mechanistic evidence that the GAST\/CCK\u2013CCKBR axis is functionally important during human endoderm and pancreas development. This pathway is repeatedly required during in vitro pluripotent stem cell differentiation, regulating germ-layer formation as well as ductal vs endocrine fate decisions. These findings support the optimisation of pancreatic differentiation protocols and inform future studies on whether this axis contributes to human pancreas development and disease.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s00125-026-06905-0","type":"journal-article","created":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T14:55:01Z","timestamp":1792508101000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["CCKBR signalling controls human definitive endoderm specification and pancreatic lineage differentiation"],"prefix":"10.1007","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-0297-050X","authenticated-orcid":false,"given":"Lama","family":"Saber","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kei","family":"Kozawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9990-5760","authenticated-orcid":false,"given":"Christos","family":"Karampelias","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0671-4114","authenticated-orcid":false,"given":"Changying","family":"Jing","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica","family":"Jaki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-0418-2333","authenticated-orcid":false,"given":"Melis","family":"Akg\u00fcn Canan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Sterr","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4368-4305","authenticated-orcid":false,"given":"Osvaldo","family":"Rodrigues Pereira","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1767-658X","authenticated-orcid":false,"given":"Oliver","family":"Czarnecki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9690-4351","authenticated-orcid":false,"given":"Gregory S.","family":"Korbutt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2227-4446","authenticated-orcid":false,"given":"Andrew R.","family":"Pepper","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-6190-2648","authenticated-orcid":false,"given":"Noel","family":"Moya","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ingo","family":"Burtscher","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4597-8825","authenticated-orcid":false,"given":"Heiko","family":"Lickert","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2307-1122","authenticated-orcid":false,"given":"Mostafa","family":"Bakhti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,10,20]]},"reference":[{"issue":"1","key":"6905_CR1","doi-asserted-by":"publisher","first-page":"e70048","DOI":"10.1111\/1753-0407.70048","volume":"17","author":"X Wang","year":"2025","unstructured":"Wang X, Zeng Z, Li D et al (2025) Advancements and challenges in immune protection strategies for islet transplantation. 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Catani and E. Schl\u00fcssel (Helmholtz Munich) for the helpful comments and discussion; A. Bastidas-Ponce, A. Shahryari, P. Cota, K. Diemer, I. Kunze, E. V. Baumgart (all Helmholtz Munich) and K. Seeberger (University of Alberta, Edmonton, AB, Canada) for technical support; and D. M. Thomson (Helmholtz Munich) for administrative support. We acknowledge the technical support of Core Facility Genomics at Helmholtz Munich. The graphical abstract and other schematic figures were generated with BioRender.com. We disclose that ChatGPT and Claude were used only for language editing of the manuscript; all content was reviewed and approved by the authors.","order":1,"name":"Ethics","label":"Acknowledgements","group":{"name":"EthicsHeading","label":"Ethics"}},{"value":"Raw bulk RNA-seq reads were uploaded to SRA with accession number PRJNA1440183. The raw and processed scRNA-seq data generated in this study have been deposited in the GEO database and are available under accession number GSE327505.","order":2,"name":"Ethics","label":"Data availability","group":{"name":"EthicsHeading","label":"Ethics"}},{"value":"Open Access funding enabled and organized by Projekt DEAL. The work was supported by the Helmholtz Society, Helmholtz Portfolio Theme 'Metabolic Dysfunction and Common Disease'. The work was also funded by research grants from the German Center for Diabetes Research (DZD e.V.) (MB), EFSD and Lilly European Diabetes Research Programme (MB), and Breakthrough T1D (3-SRA-2023-1420-S-B). LS was supported by the Helmholtz Research School for Diabetes (HRD), which is funded by the Helmholtz Association \u2013 Initiative and Networking Fund (INF). CK has received funding from the European Union's Horizon Europe research and innovation programme under the Marie Sk\u0142odowska-Curie grant agreement 101108496. CJ was supported by a scholarship under the State Scholarship Fund by the China Scholarship Council (File No. 202208080154).","order":3,"name":"Ethics","label":"Funding","group":{"name":"EthicsHeading","label":"Ethics"}},{"value":"NM is a co-founder and Chief Scientific Officer of Delphi Stem, Inc., a company developing stem cell-based therapies for diabetes.","order":4,"name":"Ethics","label":"Authors\u2019 relationships and activities","group":{"name":"EthicsHeading","label":"Ethics"}},{"value":"LS conceived the study, performed the experiments, analysed the data and drafted the manuscript. KK contributed to methodology and generation of CCKBR-targeted samples and their characterisation. CK performed bulk and scRNA-seq data analysis and contributed to manuscript preparation. CJ and MS generated scRNA-seq libraries and performed data analysis. JJ, MAC and ORP contributed to methodology and acquisition and analysis of data. OC performed image acquisition and analysis. GSK and ARP contributed to the conception of the study and the interpretation of the data. NM contributed to the conception of the study and generated preliminary data. IB contributed to and supervised the generation of CCKBR-targeted samples. HL contributed to the conception and design of the study, supervised the study, provided resources, acquired funding and critically revised the manuscript for important intellectual content. MB conceived and supervised the study, acquired funding and wrote the manuscript. All authors revised the manuscript critically for important intellectual content and approved the final version to be published. LS, HL and MB are responsible for the integrity of the work as a whole.","order":5,"name":"Ethics","label":"Contribution statement","group":{"name":"EthicsHeading","label":"Ethics"}}]}}