Galectin-3 regulates hepatic progenitor cell expansion during liver injury

Wei-Chen Hsieh; Alison C Mackinnon; Wei-Yu Lu; Jonathan Jung; Luke Boulter; Neil C Henderson; Kenneth J Simpson; Baukje Schotanus; Davina Wojtacha; Tom G Bird; Claire N Medine; David C Hay; Tariq Sethi; John P Iredale; Stuart J Forbes

doi:10.1136/gutjnl-2013-306290

Galectin-3 regulates hepatic progenitor cell expansion during liver injury

Wei-Chen Hsieh, Alison C Mackinnon, Wei-Yu Lu, Jonathan Jung, Luke Boulter, Neil C Henderson, Kenneth J Simpson, Baukje Schotanus, Davina Wojtacha, Tom G Bird, Claire N Medine, David C Hay, Tariq Sethi, John P Iredale, Stuart J Forbes^*

^*Corresponding author for this work

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

Abstract / Description of output

Objective: Following chronic liver injury or when hepatocyte proliferation is impaired, ductular reactions containing hepatic progenitor cells (HPCs) appear in the periportal regions and can regenerate the liver parenchyma. HPCs exist in a niche composed of myofibroblasts, macrophages and laminin matrix. Galectin-3 (Gal-3) is a β-galactoside-binding lectin that binds to laminin and is expressed in injured liver in mice and humans.

Design: We examined the role of Gal-3 in HPC activation. HPC activation was studied following dietary induced hepatocellular (choline-deficient ethionine-supplemented diet) and biliary (3,5-diethoxycarbonyl-1,4-dihydrocollidine supplemented diet) injury in wild type and Gal-3(-/-) mice.

Results: HPC proliferation was significantly reduced in Gal-3(-/-) mice. Gal-3(-/-) mice failed to form a HPC niche, with reduced laminin formation. HPCs isolated from wild type mice secrete Gal-3 which enhanced adhesion and proliferation of HPCs on laminin in an undifferentiated form. These effects were attenuated in Gal3(-/-) HPCs and in wild type HPCs treated with the Gal-3 inhibitor lactose. Gal-3(-/-) HPCs in vitro showed increased hepatocyte function and prematurely upregulated both biliary and hepatocyte differentiation markers and regulated cell cycle genes leading to arrest in G0/G1.

Conclusions: We conclude that Gal-3 is required for the undifferentiated expansion of HPCs in their niche in injured liver.

Original language	English
Pages (from-to)	312-321
Number of pages	10
Journal	Gut
Volume	64
Issue number	2
Early online date	16 May 2014
DOIs	https://doi.org/10.1136/gutjnl-2013-306290
Publication status	Published - Feb 2015

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10.1136/gutjnl-2013-306290

Autologous macrophage therapy promotes stem cell-mediated liver regeneration: a novel therapy for end-stage liver disease
Forbes, S. & Iredale, J.
MRC
1/02/11 → 30/09/14
Project: Research
Stem cell therapy for liver cirrhosis
Forbes, S.
UK-based charities
1/10/07 → 30/09/15
Project: Research

Neil Henderson
- Neil.Hendersoned.acuk
- Deanery of Clinical Sciences - Personal Chair of Tissue Repair and Regeneration
- Centre for Inflammation Research
Person: Academic: Research Active (Research Assistant)

Cite this

@article{33067c6c17984bd1a8cf59a9458aae2b,

title = "Galectin-3 regulates hepatic progenitor cell expansion during liver injury",

abstract = "Objective: Following chronic liver injury or when hepatocyte proliferation is impaired, ductular reactions containing hepatic progenitor cells (HPCs) appear in the periportal regions and can regenerate the liver parenchyma. HPCs exist in a niche composed of myofibroblasts, macrophages and laminin matrix. Galectin-3 (Gal-3) is a β-galactoside-binding lectin that binds to laminin and is expressed in injured liver in mice and humans.Design: We examined the role of Gal-3 in HPC activation. HPC activation was studied following dietary induced hepatocellular (choline-deficient ethionine-supplemented diet) and biliary (3,5-diethoxycarbonyl-1,4-dihydrocollidine supplemented diet) injury in wild type and Gal-3(-/-) mice.Results: HPC proliferation was significantly reduced in Gal-3(-/-) mice. Gal-3(-/-) mice failed to form a HPC niche, with reduced laminin formation. HPCs isolated from wild type mice secrete Gal-3 which enhanced adhesion and proliferation of HPCs on laminin in an undifferentiated form. These effects were attenuated in Gal3(-/-) HPCs and in wild type HPCs treated with the Gal-3 inhibitor lactose. Gal-3(-/-) HPCs in vitro showed increased hepatocyte function and prematurely upregulated both biliary and hepatocyte differentiation markers and regulated cell cycle genes leading to arrest in G0/G1.Conclusions: We conclude that Gal-3 is required for the undifferentiated expansion of HPCs in their niche in injured liver.",

author = "Wei-Chen Hsieh and Mackinnon, {Alison C} and Wei-Yu Lu and Jonathan Jung and Luke Boulter and Henderson, {Neil C} and Simpson, {Kenneth J} and Baukje Schotanus and Davina Wojtacha and Bird, {Tom G} and Medine, {Claire N} and Hay, {David C} and Tariq Sethi and Iredale, {John P} and Forbes, {Stuart J}",

note = "Funding Sir Jules Thorn Trust. Grant No. R40362, MRC (UK) Grant No. RA1486",

year = "2015",

month = feb,

doi = "10.1136/gutjnl-2013-306290",

language = "English",

volume = "64",

pages = "312--321",

journal = "Gut",

issn = "0017-5749",

publisher = "BMJ Publishing Group",

number = "2",

}

TY - JOUR

T1 - Galectin-3 regulates hepatic progenitor cell expansion during liver injury

AU - Hsieh, Wei-Chen

AU - Mackinnon, Alison C

AU - Lu, Wei-Yu

AU - Jung, Jonathan

AU - Boulter, Luke

AU - Henderson, Neil C

AU - Simpson, Kenneth J

AU - Schotanus, Baukje

AU - Wojtacha, Davina

AU - Bird, Tom G

AU - Medine, Claire N

AU - Hay, David C

AU - Sethi, Tariq

AU - Iredale, John P

AU - Forbes, Stuart J

N1 - Funding Sir Jules Thorn Trust. Grant No. R40362, MRC (UK) Grant No. RA1486

PY - 2015/2

Y1 - 2015/2

N2 - Objective: Following chronic liver injury or when hepatocyte proliferation is impaired, ductular reactions containing hepatic progenitor cells (HPCs) appear in the periportal regions and can regenerate the liver parenchyma. HPCs exist in a niche composed of myofibroblasts, macrophages and laminin matrix. Galectin-3 (Gal-3) is a β-galactoside-binding lectin that binds to laminin and is expressed in injured liver in mice and humans.Design: We examined the role of Gal-3 in HPC activation. HPC activation was studied following dietary induced hepatocellular (choline-deficient ethionine-supplemented diet) and biliary (3,5-diethoxycarbonyl-1,4-dihydrocollidine supplemented diet) injury in wild type and Gal-3(-/-) mice.Results: HPC proliferation was significantly reduced in Gal-3(-/-) mice. Gal-3(-/-) mice failed to form a HPC niche, with reduced laminin formation. HPCs isolated from wild type mice secrete Gal-3 which enhanced adhesion and proliferation of HPCs on laminin in an undifferentiated form. These effects were attenuated in Gal3(-/-) HPCs and in wild type HPCs treated with the Gal-3 inhibitor lactose. Gal-3(-/-) HPCs in vitro showed increased hepatocyte function and prematurely upregulated both biliary and hepatocyte differentiation markers and regulated cell cycle genes leading to arrest in G0/G1.Conclusions: We conclude that Gal-3 is required for the undifferentiated expansion of HPCs in their niche in injured liver.

AB - Objective: Following chronic liver injury or when hepatocyte proliferation is impaired, ductular reactions containing hepatic progenitor cells (HPCs) appear in the periportal regions and can regenerate the liver parenchyma. HPCs exist in a niche composed of myofibroblasts, macrophages and laminin matrix. Galectin-3 (Gal-3) is a β-galactoside-binding lectin that binds to laminin and is expressed in injured liver in mice and humans.Design: We examined the role of Gal-3 in HPC activation. HPC activation was studied following dietary induced hepatocellular (choline-deficient ethionine-supplemented diet) and biliary (3,5-diethoxycarbonyl-1,4-dihydrocollidine supplemented diet) injury in wild type and Gal-3(-/-) mice.Results: HPC proliferation was significantly reduced in Gal-3(-/-) mice. Gal-3(-/-) mice failed to form a HPC niche, with reduced laminin formation. HPCs isolated from wild type mice secrete Gal-3 which enhanced adhesion and proliferation of HPCs on laminin in an undifferentiated form. These effects were attenuated in Gal3(-/-) HPCs and in wild type HPCs treated with the Gal-3 inhibitor lactose. Gal-3(-/-) HPCs in vitro showed increased hepatocyte function and prematurely upregulated both biliary and hepatocyte differentiation markers and regulated cell cycle genes leading to arrest in G0/G1.Conclusions: We conclude that Gal-3 is required for the undifferentiated expansion of HPCs in their niche in injured liver.

U2 - 10.1136/gutjnl-2013-306290

DO - 10.1136/gutjnl-2013-306290

M3 - Article

C2 - 24837171

SN - 0017-5749

VL - 64

SP - 312

EP - 321

JO - Gut

JF - Gut

IS - 2

ER -

Galectin-3 regulates hepatic progenitor cell expansion during liver injury

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Autologous macrophage therapy promotes stem cell-mediated liver regeneration: a novel therapy for end-stage liver disease

Stem cell therapy for liver cirrhosis

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Neil Henderson

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