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^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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
Early online date	1 Jan 2024
DOIs	https://doi.org/10.1016/j.cell.2024.10.044
Publication status	Published - 26 Dec 2024

Keywords

acinar cells
development
endocrine cells
fetal pancreas
human organoids
LGR5
organoids
pancreas
stem cell
tripotent stem cell

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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

@article{58c57ad15a96442a9f5943bec19d9ec2,

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 = "acinar cells, development, endocrine cells, fetal pancreas, human organoids, LGR5, organoids, pancreas, stem cell, tripotent stem cell",

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",

note = "Funding Information: The authors are grateful to the women donating tissue for research. We also thank the team approaching patients for consent. A.A.-R. was also supported by an EMBO long-term fellowship (ALTF-332-2018). We thank Stefan van der Elst and Reinier van der Linden for FACS assistance and Tessa Doelman and Juri Juksar for providing reagents. Publisher Copyright: {\textcopyright} 2024 The Author(s)",

year = "2024",

month = dec,

day = "26",

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

language = "English",

volume = "187",

pages = "7394--7413.e22",

journal = "Cell",

issn = "0092-8674",

publisher = "Elsevier B.V.",

number = "26",

}

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

N1 - Funding Information: The authors are grateful to the women donating tissue for research. We also thank the team approaching patients for consent. A.A.-R. was also supported by an EMBO long-term fellowship (ALTF-332-2018). We thank Stefan van der Elst and Reinier van der Linden for FACS assistance and Tessa Doelman and Juri Juksar for providing reagents. Publisher Copyright: © 2024 The Author(s)

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 - acinar cells

KW - development

KW - endocrine cells

KW - fetal pancreas

KW - human organoids

KW - LGR5

KW - organoids

KW - pancreas

KW - stem cell

KW - tripotent stem cell

U2 - 10.1016/j.cell.2024.10.044

DO - 10.1016/j.cell.2024.10.044

M3 - Article

SN - 0092-8674

VL - 187

SP - 7394-7413.e22

JO - Cell

JF - Cell

IS - 26

ER -

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

Abstract

Keywords

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