{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,29]],"date-time":"2026-06-29T19:49:20Z","timestamp":1782762560946,"version":"3.54.5"},"reference-count":25,"publisher":"American Diabetes Association","issue":"3","license":[{"start":{"date-parts":[[2024,11,27]],"date-time":"2024-11-27T00:00:00Z","timestamp":1732665600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.diabetesjournals.org\/journals\/pages\/license"}],"funder":[{"DOI":"10.13039\/501100002915","name":"Fondation pour la Recherche Medicale","doi-asserted-by":"crossref","award":["EQU201903007793"],"award-info":[{"award-number":["EQU201903007793"]}],"id":[{"id":"10.13039\/501100002915","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001677","name":"Inserm","doi-asserted-by":"crossref","award":["874839"],"award-info":[{"award-number":["874839"]}],"id":[{"id":"10.13039\/501100001677","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100000780","name":"European Union","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100000780","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Laboratoire d\u2019Excellence consortium Revive"},{"DOI":"10.13039\/100019009","name":"Fondation Francophone pour la Recherche sur le Diabete","doi-asserted-by":"crossref","award":["ANR-10-LABX-73-01"],"award-info":[{"award-number":["ANR-10-LABX-73-01"]}],"id":[{"id":"10.13039\/100019009","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001665","name":"Agence Nationale de la Recherche","doi-asserted-by":"publisher","award":["ANR-19-CE16-0021-01"],"award-info":[{"award-number":["ANR-19-CE16-0021-01"]}],"id":[{"id":"10.13039\/501100001665","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["diabetesjournals.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2025,3,1]]},"abstract":"<jats:sec>\n                    <jats:title\/>\n                    <jats:p>Murine pancreatic endocrinogenesis has been extensively studied, but human data remain scarce due to limited sample availability. Here, we first built a large collection of human embryonic and fetal pancreases covering the first trimester of pregnancy to explore human endocrinogenesis. Using an experimental pipeline combining in toto staining, tissue clearing, and light-sheet fluorescence microscopy, we show that insulin-, glucagon-, and somatostatin-positive cells appear simultaneously at Carnegie stage (CS) 16. This contrasts with rodents, in which glucagon-positive cells appear first, followed by insulin-positive and, finally, somatostatin-positive cells and highlights interspecies differences. We also detected bihormonal endocrine cells in 7 of 9 human pancreases between CS16 and CS18, which were no longer detected at later stages. We observed that cell distribution within human fetal islets resembles adult mouse islets, with a core of \u03b2-cells surrounded by \u03b1- and \u03b4-cells, differing from a more complex arrangement in adult human islets. This, in connection with the small size of human fetal islets when compared with adult islets, suggests that adult human islets may form by fusion of preexisting islets, in contrast to the mouse fission model. Together, our study provides a detailed and comprehensive description of the spatiotemporal dynamics of human pancreatic endocrinogenesis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Article Highlights<\/jats:title>\n                    <jats:p>Data on human pancreas development are limited and derived from two-dimensional staining. We overcome this using in toto staining, tissue clearing, and light-sheet imaging. We sought to understand when and where endocrine cells first emerge and how they cluster. First, endocrine cell types appear simultaneously, and early pancreases contain bihormonal cells. There are morphometric differences between fetal and adult islets. We propose a mechanism of adult islet formation by fusion: a new base to reconstitute in\u00a0vitro islet neogenesis.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.2337\/db24-0641","type":"journal-article","created":{"date-parts":[[2024,11,27]],"date-time":"2024-11-27T13:23:51Z","timestamp":1732713831000},"page":"368-375","update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":8,"title":["Imaging Human Pancreatic Endocrinogenesis During Early Prenatal Life"],"prefix":"10.2337","volume":"74","author":[{"given":"Adrian","family":"Villalba","sequence":"first","affiliation":[{"name":"1Institut Cochin, CNRS, INSERM, Universit\u00e9 Paris Cit\u00e9, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yorick","family":"Gitton","sequence":"additional","affiliation":[{"name":"2Inserm, CNRS, Institut de la Vision, Sorbonne Universit\u00e9, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Virginie","family":"Aiello","sequence":"additional","affiliation":[{"name":"1Institut Cochin, CNRS, INSERM, Universit\u00e9 Paris Cit\u00e9, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maryne","family":"Toupin","sequence":"additional","affiliation":[{"name":"3Inserm, EHESP, Institut de Recherche en Sant\u00e9, Environnement et Travail, UMR_S 1085, Universit\u00e9 Rennes, Rennes, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S\u00e9verine","family":"Mazaud-Guittot","sequence":"additional","affiliation":[{"name":"3Inserm, EHESP, Institut de Recherche en Sant\u00e9, Environnement et Travail, UMR_S 1085, Universit\u00e9 Rennes, Rennes, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alain","family":"Ch\u00e9dotal","sequence":"additional","affiliation":[{"name":"2Inserm, CNRS, Institut de la Vision, Sorbonne Universit\u00e9, Paris, France"},{"name":"4Institut de Pathologie, Groupe Hospitalier Est, Hospices Civils de Lyon, Lyon, France"},{"name":"5MeLiS (Mechanisms in Integrated Life Sciences), CNRS UMR5284, INSERM U1314, University Claude Bernard Lyon 1, Lyon, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7619-337X","authenticated-orcid":false,"given":"Rapha\u00ebl","family":"Scharfmann","sequence":"additional","affiliation":[{"name":"1Institut Cochin, CNRS, INSERM, Universit\u00e9 Paris Cit\u00e9, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1167","published-online":{"date-parts":[[2024,11,27]]},"reference":[{"key":"2025022019525007600_B1","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1016\/j.ydbio.2008.10.024","article-title":"Developmental biology of the pancreas: a comprehensive review","volume":"326","author":"Gittes","year":"2009","journal-title":"Dev Biol"},{"key":"2025022019525007600_B2","doi-asserted-by":"crossref","first-page":"1257","DOI":"10.1242\/dev.113.4.1257","article-title":"Embryogenesis of the murine endocrine pancreas; early expression of pancreatic polypeptide gene","volume":"113","author":"Herrera","year":"1991","journal-title":"Development"},{"key":"2025022019525007600_B3","doi-asserted-by":"crossref","first-page":"1087","DOI":"10.1369\/jhc.5C6684.2005","article-title":"Assessment of human pancreatic islet architecture and composition by laser scanning confocal microscopy","volume":"53","author":"Brissova","year":"2005","journal-title":"J Histochem Cytochem"},{"key":"2025022019525007600_B4","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1016\/j.cell.2017.03.008","article-title":"Tridimensional visualization and analysis of early human development","volume":"169","author":"Belle","year":"2017","journal-title":"Cell"},{"key":"2025022019525007600_B5","doi-asserted-by":"crossref","first-page":"1066","DOI":"10.1007\/s00125-024-06143-2","article-title":"A 3D atlas of the human developing pancreas to explore progenitor proliferation and differentiation","volume":"67","author":"Villalba","year":"2024","journal-title":"Diabetologia"},{"key":"2025022019525007600_B6","doi-asserted-by":"crossref","first-page":"676","DOI":"10.1038\/nmeth.2019","article-title":"Fiji: an open-source platform for biological-image analysis","volume":"9","author":"Schindelin","year":"2012","journal-title":"Nat Methods"},{"key":"2025022019525007600_B7","doi-asserted-by":"crossref","first-page":"1250023","DOI":"10.3389\/fendo.2023.1250023","article-title":"PyCreas: a tool for quantification of localization and distribution of endocrine cell types in the islets of Langerhans","volume":"14","author":"Asuaje Pfeifer","year":"2023","journal-title":"Front Endocrinol (Lausanne)"},{"key":"2025022019525007600_B8","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1038\/s41574-018-0132-z","article-title":"Modelling the endocrine pancreas in health and disease","volume":"15","author":"Bakhti","year":"2019","journal-title":"Nat Rev Endocrinol"},{"key":"2025022019525007600_B9","doi-asserted-by":"crossref","first-page":"3318","DOI":"10.1038\/s41467-024-47686-7","article-title":"Illuminating the complete \u03b2-cell mass of the human pancreas- signifying a new view on the islets of Langerhans","volume":"15","author":"Lehrstrand","year":"2024","journal-title":"Nat Commun"},{"key":"2025022019525007600_B10","doi-asserted-by":"crossref","first-page":"642152","DOI":"10.3389\/fendo.2021.642152","article-title":"Human pluripotent stem cells to model islet defects in diabetes","volume":"12","author":"Balboa","year":"2021","journal-title":"Front Endocrinol (Lausanne)"},{"key":"2025022019525007600_B11","doi-asserted-by":"crossref","first-page":"3514","DOI":"10.2337\/db12-1479","article-title":"Development of the human pancreas from foregut to endocrine commitment","volume":"62","author":"Jennings","year":"2013","journal-title":"Diabetes"},{"key":"2025022019525007600_B12","doi-asserted-by":"crossref","first-page":"811","DOI":"10.1369\/jhc.2009.953307","article-title":"Endocrine cell clustering during human pancreas development","volume":"57","author":"Jeon","year":"2009","journal-title":"J Histochem Cytochem"},{"key":"2025022019525007600_B13","doi-asserted-by":"crossref","first-page":"3126","DOI":"10.1242\/dev.120063","article-title":"Human pancreas development","volume":"142","author":"Jennings","year":"2015","journal-title":"Development"},{"key":"2025022019525007600_B14","doi-asserted-by":"crossref","first-page":"372","DOI":"10.1007\/s00125-011-2344-9","article-title":"Immunohistochemical characterisation of cells co-producing insulin and glucagon in the developing human pancreas","volume":"55","author":"Riedel","year":"2012","journal-title":"Diabetologia"},{"key":"2025022019525007600_B15","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1006\/dbio.2000.0103","article-title":"Pancreas development in zebrafish: early dispersed appearance of endocrine hormone expressing cells and their convergence to form the definitive islet","volume":"230","author":"Biemar","year":"2001","journal-title":"Dev Biol"},{"key":"2025022019525007600_B16","doi-asserted-by":"crossref","first-page":"685","DOI":"10.1210\/er.2007-0016","article-title":"An illustrated review of early pancreas development in the mouse","volume":"28","author":"J\u00f8rgensen","year":"2007","journal-title":"Endocr Rev"},{"key":"2025022019525007600_B17","doi-asserted-by":"crossref","first-page":"e982949","DOI":"10.4161\/19382014.2014.982949","article-title":"Ultrastructural and immunohistochemical analysis of the 8-20 week human fetal pancreas","volume":"6","author":"Riopel","year":"2014","journal-title":"Islets"},{"key":"2025022019525007600_B18","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1016\/j.cmet.2022.11.009","article-title":"Single-cell transcriptomic and spatial landscapes of the developing human pancreas","volume":"35","author":"Olaniru","year":"2023","journal-title":"Cell Metab"},{"key":"2025022019525007600_B19","doi-asserted-by":"crossref","first-page":"428","DOI":"10.1016\/j.cell.2014.09.040","article-title":"Generation of functional human pancreatic \u03b2 cells in\u00a0vitro","volume":"159","author":"Pagliuca","year":"2014","journal-title":"Cell"},{"key":"2025022019525007600_B20","doi-asserted-by":"crossref","first-page":"1115","DOI":"10.1242\/dev.112.4.1115","article-title":"Polyclonal origin of pancreatic islets in aggregation mouse chimaeras","volume":"112","author":"Deltour","year":"1991","journal-title":"Development"},{"key":"2025022019525007600_B21","doi-asserted-by":"crossref","first-page":"e3559","DOI":"10.1371\/journal.pone.0003559","article-title":"Beta cells within single human islets originate from multiple progenitors","volume":"3","author":"Scharfmann","year":"2008","journal-title":"PLoS One"},{"key":"2025022019525007600_B22","doi-asserted-by":"crossref","first-page":"dev199655","DOI":"10.1242\/dev.199655","article-title":"Development of a 3D atlas of the embryonic pancreas for topological and quantitative analysis of heterologous cell interactions","volume":"149","author":"Glorieux","year":"2022","journal-title":"Development"},{"key":"2025022019525007600_B23","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1080\/19382014.2022.2030649","article-title":"Determinants and dynamics of pancreatic islet architecture","volume":"14","author":"Adams","year":"2022","journal-title":"Islets"},{"key":"2025022019525007600_B24","doi-asserted-by":"crossref","first-page":"604","DOI":"10.1369\/0022155415570969","article-title":"Human islet morphology revisited: human and rodent islets are not so different after all","volume":"63","author":"Bonner-Weir","year":"2015","journal-title":"J Histochem Cytochem"},{"key":"2025022019525007600_B25","doi-asserted-by":"crossref","first-page":"3197","DOI":"10.1210\/jc.2012-1206","article-title":"Formation of a human \u03b2-cell population within pancreatic islets is set early in life","volume":"97","author":"Gregg","year":"2012","journal-title":"J Clin Endocrinol Metab"}],"container-title":["Diabetes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/diabetesjournals.org\/diabetes\/article-pdf\/74\/3\/368\/791022\/db240641.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/diabetesjournals.org\/diabetes\/article-pdf\/74\/3\/368\/791022\/db240641.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,2,20]],"date-time":"2025-02-20T14:53:39Z","timestamp":1740063219000},"score":1,"resource":{"primary":{"URL":"https:\/\/diabetesjournals.org\/diabetes\/article\/74\/3\/368\/157537\/Imaging-Human-Pancreatic-Endocrinogenesis-During"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,11,27]]},"references-count":25,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2024,11,27]]},"published-print":{"date-parts":[[2025,3,1]]}},"URL":"https:\/\/doi.org\/10.2337\/db24-0641","relation":{"has-preprint":[{"id-type":"doi","id":"10.2337\/figshare.27901659.v2","asserted-by":"object"},{"id-type":"doi","id":"10.2337\/figshare.27901659.v1","asserted-by":"object"},{"id-type":"doi","id":"10.2337\/figshare.27901659","asserted-by":"object"}]},"ISSN":["0012-1797","1939-327X"],"issn-type":[{"value":"0012-1797","type":"print"},{"value":"1939-327X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,11,27]]}}}