Long-term in vitro expansion of a human fetal pancreas stem cell that generates all three pancreatic cell lineages

Amanda Andersson-Rolf; Kelvin Groot; Jeroen Korving; Harry Begthel; Maaike A J Hanegraaf; Michael VanInsberghe; Fredrik Salmén; Stieneke van den Brink; Carmen Lopez-Iglesias; Peter J Peters; Daniel Krueger; Joep Beumer; Maarten H Geurts; Anna Alemany; Helmuth Gehart; Françoise Carlotti; Eelco J P de Koning; Susana M Chuva de Sousa Lopes; Alexander van Oudenaarden; Johan H van Es; Hans Clevers

doi:10.1016/j.cell.2024.10.044

Long-term in vitro expansion of a human fetal pancreas stem cell that generates all three pancreatic cell lineages

Amanda Andersson-Rolf, Kelvin Groot, Jeroen Korving, Harry Begthel, Maaike A J Hanegraaf, Michael VanInsberghe, Fredrik Salmén, Stieneke van den Brink, Carmen Lopez-Iglesias, Peter J Peters, Daniel Krueger, Joep Beumer, Maarten H Geurts, Anna Alemany, Helmuth Gehart, Françoise Carlotti, Eelco J P de Koning, Susana M Chuva de Sousa Lopes, Alexander van Oudenaarden, Johan H van EsHans Clevers

Hubrecht Institute

Research output: Contribution to journal/periodical › Article › Scientific › peer-review

2 Citations (Scopus)

Abstract

The mammalian pancreas consists of three epithelial compartments: the acini and ducts of the exocrine pancreas and the endocrine islets of Langerhans. Murine studies indicate that these three compartments derive from a transient, common pancreatic progenitor. Here, we report derivation of 18 human fetal pancreas organoid (hfPO) lines from gestational weeks 8-17 (8-17 GWs) fetal pancreas samples. Four of these lines, derived from 15 to 16 GWs samples, generate acinar-, ductal-, and endocrine-lineage cells while expanding exponentially for >2 years under optimized culture conditions. Single-cell RNA sequencing identifies rare LGR5+ cells in fetal pancreas and in hfPOs as the root of the developmental hierarchy. These LGR5+ cells share multiple markers with adult gastrointestinal tract stem cells. Organoids derived from single LGR5+ organoid-derived cells recapitulate this tripotency in vitro. We describe a human fetal tripotent stem/progenitor cell capable of long-term expansion in vitro and of generating all three pancreatic cell lineages.

Original language	English
Pages (from-to)	7394-7413.e22
Journal	Cell
Volume	187
Issue number	26
DOIs	https://doi.org/10.1016/j.cell.2024.10.044
Publication status	Published - 26 Dec 2024

Keywords

Humans
Cell Lineage
Pancreas/cytology
Organoids/cytology
Fetus/cytology
Cell Differentiation
Receptors, G-Protein-Coupled/metabolism
Fetal Stem Cells/cytology
Cell Proliferation
Single-Cell Analysis
Islets of Langerhans/cytology
Mice
Animals
Acinar Cells/cytology

Access to Document

10.1016/j.cell.2024.10.044

Cite this

Andersson-Rolf, A., Groot, K., Korving, J., Begthel, H., Hanegraaf, M. A. J., VanInsberghe, M., Salmén, F., van den Brink, S., Lopez-Iglesias, C., Peters, P. J., Krueger, D., Beumer, J., Geurts, M. H., Alemany, A., Gehart, H., Carlotti, F., de Koning, E. J. P., Chuva de Sousa Lopes, S. M., van Oudenaarden, A., ... Clevers, H. (2024). Long-term in vitro expansion of a human fetal pancreas stem cell that generates all three pancreatic cell lineages. Cell, 187(26), 7394-7413.e22. https://doi.org/10.1016/j.cell.2024.10.044

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title = "Long-term in vitro expansion of a human fetal pancreas stem cell that generates all three pancreatic cell lineages",

abstract = "The mammalian pancreas consists of three epithelial compartments: the acini and ducts of the exocrine pancreas and the endocrine islets of Langerhans. Murine studies indicate that these three compartments derive from a transient, common pancreatic progenitor. Here, we report derivation of 18 human fetal pancreas organoid (hfPO) lines from gestational weeks 8-17 (8-17 GWs) fetal pancreas samples. Four of these lines, derived from 15 to 16 GWs samples, generate acinar-, ductal-, and endocrine-lineage cells while expanding exponentially for >2 years under optimized culture conditions. Single-cell RNA sequencing identifies rare LGR5+ cells in fetal pancreas and in hfPOs as the root of the developmental hierarchy. These LGR5+ cells share multiple markers with adult gastrointestinal tract stem cells. Organoids derived from single LGR5+ organoid-derived cells recapitulate this tripotency in vitro. We describe a human fetal tripotent stem/progenitor cell capable of long-term expansion in vitro and of generating all three pancreatic cell lineages.",

keywords = "Humans, Cell Lineage, Pancreas/cytology, Organoids/cytology, Fetus/cytology, Cell Differentiation, Receptors, G-Protein-Coupled/metabolism, Fetal Stem Cells/cytology, Cell Proliferation, Single-Cell Analysis, Islets of Langerhans/cytology, Mice, Animals, Acinar Cells/cytology",

author = "Amanda Andersson-Rolf and Kelvin Groot and Jeroen Korving and Harry Begthel and Hanegraaf, {Maaike A J} and Michael VanInsberghe and Fredrik Salm{\'e}n and {van den Brink}, Stieneke and Carmen Lopez-Iglesias and Peters, {Peter J} and Daniel Krueger and Joep Beumer and Geurts, {Maarten H} and Anna Alemany and Helmuth Gehart and Fran{\c c}oise Carlotti and {de Koning}, {Eelco J P} and {Chuva de Sousa Lopes}, {Susana M} and {van Oudenaarden}, Alexander and {van Es}, {Johan H} and Hans Clevers",

year = "2024",

month = dec,

day = "26",

doi = "10.1016/j.cell.2024.10.044",

language = "English",

volume = "187",

pages = "7394--7413.e22",

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Andersson-Rolf, A, Groot, K, Korving, J, Begthel, H, Hanegraaf, MAJ, VanInsberghe, M, Salmén, F, van den Brink, S, Lopez-Iglesias, C, Peters, PJ, Krueger, D, Beumer, J, Geurts, MH, Alemany, A, Gehart, H, Carlotti, F, de Koning, EJP, Chuva de Sousa Lopes, SM, van Oudenaarden, A , van Es, JH & Clevers, H 2024, 'Long-term in vitro expansion of a human fetal pancreas stem cell that generates all three pancreatic cell lineages', Cell, vol. 187, no. 26, pp. 7394-7413.e22. https://doi.org/10.1016/j.cell.2024.10.044

TY - JOUR

T1 - Long-term in vitro expansion of a human fetal pancreas stem cell that generates all three pancreatic cell lineages

AU - Andersson-Rolf, Amanda

AU - Groot, Kelvin

AU - Korving, Jeroen

AU - Begthel, Harry

AU - Hanegraaf, Maaike A J

AU - VanInsberghe, Michael

AU - Salmén, Fredrik

AU - van den Brink, Stieneke

AU - Lopez-Iglesias, Carmen

AU - Peters, Peter J

AU - Krueger, Daniel

AU - Beumer, Joep

AU - Geurts, Maarten H

AU - Alemany, Anna

AU - Gehart, Helmuth

AU - Carlotti, Françoise

AU - de Koning, Eelco J P

AU - Chuva de Sousa Lopes, Susana M

AU - van Oudenaarden, Alexander

AU - van Es, Johan H

AU - Clevers, Hans

PY - 2024/12/26

Y1 - 2024/12/26

N2 - The mammalian pancreas consists of three epithelial compartments: the acini and ducts of the exocrine pancreas and the endocrine islets of Langerhans. Murine studies indicate that these three compartments derive from a transient, common pancreatic progenitor. Here, we report derivation of 18 human fetal pancreas organoid (hfPO) lines from gestational weeks 8-17 (8-17 GWs) fetal pancreas samples. Four of these lines, derived from 15 to 16 GWs samples, generate acinar-, ductal-, and endocrine-lineage cells while expanding exponentially for >2 years under optimized culture conditions. Single-cell RNA sequencing identifies rare LGR5+ cells in fetal pancreas and in hfPOs as the root of the developmental hierarchy. These LGR5+ cells share multiple markers with adult gastrointestinal tract stem cells. Organoids derived from single LGR5+ organoid-derived cells recapitulate this tripotency in vitro. We describe a human fetal tripotent stem/progenitor cell capable of long-term expansion in vitro and of generating all three pancreatic cell lineages.

AB - The mammalian pancreas consists of three epithelial compartments: the acini and ducts of the exocrine pancreas and the endocrine islets of Langerhans. Murine studies indicate that these three compartments derive from a transient, common pancreatic progenitor. Here, we report derivation of 18 human fetal pancreas organoid (hfPO) lines from gestational weeks 8-17 (8-17 GWs) fetal pancreas samples. Four of these lines, derived from 15 to 16 GWs samples, generate acinar-, ductal-, and endocrine-lineage cells while expanding exponentially for >2 years under optimized culture conditions. Single-cell RNA sequencing identifies rare LGR5+ cells in fetal pancreas and in hfPOs as the root of the developmental hierarchy. These LGR5+ cells share multiple markers with adult gastrointestinal tract stem cells. Organoids derived from single LGR5+ organoid-derived cells recapitulate this tripotency in vitro. We describe a human fetal tripotent stem/progenitor cell capable of long-term expansion in vitro and of generating all three pancreatic cell lineages.

KW - Humans

KW - Cell Lineage

KW - Pancreas/cytology

KW - Organoids/cytology

KW - Fetus/cytology

KW - Cell Differentiation

KW - Receptors, G-Protein-Coupled/metabolism

KW - Fetal Stem Cells/cytology

KW - Cell Proliferation

KW - Single-Cell Analysis

KW - Islets of Langerhans/cytology

KW - Mice

KW - Animals

KW - Acinar Cells/cytology

U2 - 10.1016/j.cell.2024.10.044

DO - 10.1016/j.cell.2024.10.044

M3 - Article

C2 - 39626658

SN - 0092-8674

VL - 187

SP - 7394-7413.e22

JO - Cell

JF - Cell

IS - 26

ER -