Long-Term Culture of Genome-Stable Bipotent Stem Cells from Adult Human Liver

Meritxell Huch; Helmuth Gehart; Ruben van Boxtel; Karien Hamer; Francis Blokzijl; Monique M. A. Verstegen; Ewa Ellis; Martien van Wenum; Sabine A. Fuchs; Joep de Ligt; Marc van de Wetering; Nobuo Sasaki; Susanne J. Boers; Hans Kemperman; Jeroen de Jonge; Jan N. M. Ijzermans; Edward E. S. Nieuwenhuis; Ruurdtje Hoekstra; Stephen Strom; Robert R. G.  Vries; Luc J. W. van der Laan; Edwin Cuppen; Hans Clevers

doi:10.1016/j.cell.2014.11.050

Long-Term Culture of Genome-Stable Bipotent Stem Cells from Adult Human Liver

Meritxell Huch^*, Helmuth Gehart, Ruben van Boxtel, Karien Hamer, Francis Blokzijl, Monique M. A. Verstegen, Ewa Ellis, Martien van Wenum, Sabine A. Fuchs, Joep de Ligt, Marc van de Wetering, Nobuo Sasaki, Susanne J. Boers, Hans Kemperman, Jeroen de Jonge, Jan N. M. Ijzermans, Edward E. S. Nieuwenhuis, Ruurdtje Hoekstra, Stephen Strom, Robert R. G. VriesLuc J. W. van der Laan, Edwin Cuppen, Hans Clevers

^*Corresponding author for this work

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

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Abstract

Despite the enormous replication potential of the human liver, there are currently no culture systems available that sustain hepatocyte replication and/or function in vitro. We have shown previously that single mouse Lgr5+ liver stem cells can be expanded as epithelial organoids in vitro and can be differentiated into functional hepatocytes in vitro and in vivo. We now describe conditions allowing long-term expansion of adult bile duct-derived bipotent progenitor cells from human liver. The expanded cells are highly stable at the chromosome and structural level, while single base changes occur at very low rates. The cells can readily be converted into functional hepatocytes in vitro and upon transplantation in vivo. Organoids from alpha 1-antitrypsin deficiency and Alagille syndrome patients mirror the in vivo pathology. Clonal long-term expansion of primary adult liver stem cells opens up experimental avenues for disease modeling, toxicology studies, regenerative medicine, and gene therapy.

Original language	English
Pages (from-to)	299-312
Number of pages	14
Journal	Cell
Volume	160
Issue number	1-2
DOIs	https://doi.org/10.1016/j.cell.2014.11.050
Publication status	Published - 15 Jan 2015

Keywords

IN-VITRO EXPANSION
COPY NUMBER
ALPHA-1-ANTITRYPSIN DEFICIENCY
ALAGILLE-SYNDROME
MOUSE MODEL
HEPATOCYTES
REGENERATION
LGR5
DIFFERENTIATION
IDENTIFICATION
Organ Culture Techniques
Genomic Instability
Liver
Animals
Humans
Organoids
Mice

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Huch, M., Gehart, H., van Boxtel, R., Hamer, K., Blokzijl, F., Verstegen, M. M. A., Ellis, E., van Wenum, M., Fuchs, S. A., de Ligt, J., van de Wetering, M., Sasaki, N., Boers, S. J., Kemperman, H., de Jonge, J., Ijzermans, J. N. M., Nieuwenhuis, E. E. S., Hoekstra, R., Strom, S., ... Clevers, H. (2015). Long-Term Culture of Genome-Stable Bipotent Stem Cells from Adult Human Liver. Cell, 160(1-2), 299-312. https://doi.org/10.1016/j.cell.2014.11.050

@article{5844cb44944c4519a950d59dc23f7896,

title = "Long-Term Culture of Genome-Stable Bipotent Stem Cells from Adult Human Liver",

abstract = "Despite the enormous replication potential of the human liver, there are currently no culture systems available that sustain hepatocyte replication and/or function in vitro. We have shown previously that single mouse Lgr5+ liver stem cells can be expanded as epithelial organoids in vitro and can be differentiated into functional hepatocytes in vitro and in vivo. We now describe conditions allowing long-term expansion of adult bile duct-derived bipotent progenitor cells from human liver. The expanded cells are highly stable at the chromosome and structural level, while single base changes occur at very low rates. The cells can readily be converted into functional hepatocytes in vitro and upon transplantation in vivo. Organoids from alpha 1-antitrypsin deficiency and Alagille syndrome patients mirror the in vivo pathology. Clonal long-term expansion of primary adult liver stem cells opens up experimental avenues for disease modeling, toxicology studies, regenerative medicine, and gene therapy.",

keywords = "IN-VITRO EXPANSION, COPY NUMBER, ALPHA-1-ANTITRYPSIN DEFICIENCY, ALAGILLE-SYNDROME, MOUSE MODEL, HEPATOCYTES, REGENERATION, LGR5, DIFFERENTIATION, IDENTIFICATION, Organ Culture Techniques, Genomic Instability, Liver, Animals, Humans, Organoids, Mice",

author = "Meritxell Huch and Helmuth Gehart and {van Boxtel}, Ruben and Karien Hamer and Francis Blokzijl and Verstegen, {Monique M. A.} and Ewa Ellis and {van Wenum}, Martien and Fuchs, {Sabine A.} and {de Ligt}, Joep and {van de Wetering}, Marc and Nobuo Sasaki and Boers, {Susanne J.} and Hans Kemperman and {de Jonge}, Jeroen and Ijzermans, {Jan N. M.} and Nieuwenhuis, {Edward E. S.} and Ruurdtje Hoekstra and Stephen Strom and Vries, {Robert R. G.} and {van der Laan}, {Luc J. W.} and Edwin Cuppen and Hans Clevers",

year = "2015",

month = jan,

day = "15",

doi = "10.1016/j.cell.2014.11.050",

language = "English",

volume = "160",

pages = "299--312",

number = "1-2",

}

Huch, M, Gehart, H, van Boxtel, R, Hamer, K, Blokzijl, F, Verstegen, MMA, Ellis, E, van Wenum, M, Fuchs, SA, de Ligt, J, van de Wetering, M, Sasaki, N, Boers, SJ, Kemperman, H, de Jonge, J, Ijzermans, JNM, Nieuwenhuis, EES, Hoekstra, R, Strom, S, Vries, RRG, van der Laan, LJW, Cuppen, E & Clevers, H 2015, 'Long-Term Culture of Genome-Stable Bipotent Stem Cells from Adult Human Liver', Cell, vol. 160, no. 1-2, pp. 299-312. https://doi.org/10.1016/j.cell.2014.11.050

TY - JOUR

T1 - Long-Term Culture of Genome-Stable Bipotent Stem Cells from Adult Human Liver

AU - Huch, Meritxell

AU - Gehart, Helmuth

AU - van Boxtel, Ruben

AU - Hamer, Karien

AU - Blokzijl, Francis

AU - Verstegen, Monique M. A.

AU - Ellis, Ewa

AU - van Wenum, Martien

AU - Fuchs, Sabine A.

AU - de Ligt, Joep

AU - van de Wetering, Marc

AU - Sasaki, Nobuo

AU - Boers, Susanne J.

AU - Kemperman, Hans

AU - de Jonge, Jeroen

AU - Ijzermans, Jan N. M.

AU - Nieuwenhuis, Edward E. S.

AU - Hoekstra, Ruurdtje

AU - Strom, Stephen

AU - Vries, Robert R. G.

AU - van der Laan, Luc J. W.

AU - Cuppen, Edwin

AU - Clevers, Hans

PY - 2015/1/15

Y1 - 2015/1/15

N2 - Despite the enormous replication potential of the human liver, there are currently no culture systems available that sustain hepatocyte replication and/or function in vitro. We have shown previously that single mouse Lgr5+ liver stem cells can be expanded as epithelial organoids in vitro and can be differentiated into functional hepatocytes in vitro and in vivo. We now describe conditions allowing long-term expansion of adult bile duct-derived bipotent progenitor cells from human liver. The expanded cells are highly stable at the chromosome and structural level, while single base changes occur at very low rates. The cells can readily be converted into functional hepatocytes in vitro and upon transplantation in vivo. Organoids from alpha 1-antitrypsin deficiency and Alagille syndrome patients mirror the in vivo pathology. Clonal long-term expansion of primary adult liver stem cells opens up experimental avenues for disease modeling, toxicology studies, regenerative medicine, and gene therapy.

AB - Despite the enormous replication potential of the human liver, there are currently no culture systems available that sustain hepatocyte replication and/or function in vitro. We have shown previously that single mouse Lgr5+ liver stem cells can be expanded as epithelial organoids in vitro and can be differentiated into functional hepatocytes in vitro and in vivo. We now describe conditions allowing long-term expansion of adult bile duct-derived bipotent progenitor cells from human liver. The expanded cells are highly stable at the chromosome and structural level, while single base changes occur at very low rates. The cells can readily be converted into functional hepatocytes in vitro and upon transplantation in vivo. Organoids from alpha 1-antitrypsin deficiency and Alagille syndrome patients mirror the in vivo pathology. Clonal long-term expansion of primary adult liver stem cells opens up experimental avenues for disease modeling, toxicology studies, regenerative medicine, and gene therapy.

KW - IN-VITRO EXPANSION

KW - COPY NUMBER

KW - ALPHA-1-ANTITRYPSIN DEFICIENCY

KW - ALAGILLE-SYNDROME

KW - MOUSE MODEL

KW - HEPATOCYTES

KW - REGENERATION

KW - LGR5

KW - DIFFERENTIATION

KW - IDENTIFICATION

KW - Organ Culture Techniques

KW - Genomic Instability

KW - Liver

KW - Animals

KW - Humans

KW - Organoids

KW - Mice

U2 - 10.1016/j.cell.2014.11.050

DO - 10.1016/j.cell.2014.11.050

M3 - Article

C2 - 25533785

SN - 0092-8674

VL - 160

SP - 299

EP - 312

JO - Cell

JF - Cell

IS - 1-2

ER -

Long-Term Culture of Genome-Stable Bipotent Stem Cells from Adult Human Liver

Abstract

Keywords

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