Paracrine cellular senescence exacerbates biliary injury and impairs regeneration

Sofia Ferreira-Gonzalez; Wei-yu Lu; Alexander Raven; Benjamin Dwyer; Tak Yung Man; Eoghan O’Duibhir; Philip J. Starkey Lewis; Lara Campana; Tim J. Kendall; Thomas G. Bird; Nuria Tarrats; Juan-Carlos Acosta; Luke Boulter; Stuart J. Forbes

doi:10.1038/s41467-018-03299-5

Paracrine cellular senescence exacerbates biliary injury and impairs regeneration

Sofia Ferreira-Gonzalez, Wei-yu Lu, Alexander Raven, Benjamin Dwyer, Tak Yung Man, Eoghan O’Duibhir, Philip J. Starkey Lewis, Lara Campana, Tim J. Kendall, Thomas G. Bird, Nuria Tarrats, Juan-Carlos Acosta, Luke Boulter, Stuart J. Forbes

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

Abstract / Description of output

Cellular senescence is a mechanism that provides an irreversible barrier to cell cycle progression
to prevent undesired proliferation. However, under pathological circumstances,
senescence can adversely affect organ function, viability and regeneration. We have developed
a mouse model of biliary senescence, based on the conditional deletion of Mdm2 in bile
ducts under the control of the Krt19 promoter, that exhibits features of biliary disease. Here
we report that senescent cholangiocytes induce profound alterations in the cellular and
signalling microenvironment, with recruitment of myofibroblasts and macrophages causing
collagen deposition, TGFβ production and induction of senescence in surrounding cholangiocytes
and hepatocytes. Finally, we study how inhibition of TGFβ-signalling disrupts the
transmission of senescence and restores liver function. We identify cellular senescence as a
detrimental mechanism in the development of biliary injury. Our results identify TGFβ as a
potential therapeutic target to limit senescence-dependent aggravation in human
cholangiopathies.

Original language	English
Article number	1020
Journal	Nature Communications
Volume	9
Issue number	1
DOIs	https://doi.org/10.1038/s41467-018-03299-5
Publication status	Published - 9 Mar 2018

Keywords / Materials (for Non-textual outputs)

Bile ducts
Liver fibrosis
Mechanisms of disease
Senescence

Access to Document

10.1038/s41467-018-03299-5

s41467-018-03299-5
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Final published version, 13.1 MBLicence: Creative Commons: Attribution (CC-BY)

http://www.nature.com/articles/s41467-018-03299-5

The Computational and Chemical Biology of the Stem Cell Niche
Forbes, S.
MRC
1/01/14 → 31/03/15
Project: Research
A HUB FOR ENGINEERING AND EXPLOITING THE STEM CELL NICHE
Forbes, S.
MRC
1/11/13 → 31/03/18
Project: Research
MRC Centre Grant Renewal
Ffrench-Constant, C. & Forbes, S.
MRC
1/05/13 → 30/04/18
Project: Research

CRM researchers have discovered a potential new target for the treatment of a type of liver disease that affects the bile ducts.
Sofia Ferreira Gonzalez
9/03/18
1 Media contribution
Press/Media: Press Release

Juan-Carlos Acosta
- Deanery of Molecular, Genetic and Population Health Sciences - Visitor: Staff Non UK HEI
Person: Affiliated Independent Researcher
Tom Bird
- Deanery of Clinical Sciences - Personal Chair of Hepatobiliary Cancer
- Centre for Inflammation Research
Person: Academic: Research Active
Luke Boulter
- Deanery of Molecular, Genetic and Population Health Sciences - Reader
- MRC Human Genetics Unit
Person: Academic: Research Active

Cite this

Ferreira-Gonzalez, S., Lu, W., Raven, A., Dwyer, B., Man, T. Y., O’Duibhir, E., Lewis, P. J. S., Campana, L., Kendall, T. J., Bird, T. G., Tarrats, N., Acosta, J.-C., Boulter, L., & Forbes, S. J. (2018). Paracrine cellular senescence exacerbates biliary injury and impairs regeneration. Nature Communications, 9(1), Article 1020. https://doi.org/10.1038/s41467-018-03299-5

@article{6d826c39458f4c6280170994d227504d,

title = "Paracrine cellular senescence exacerbates biliary injury and impairs regeneration",

abstract = "Cellular senescence is a mechanism that provides an irreversible barrier to cell cycle progressionto prevent undesired proliferation. However, under pathological circumstances,senescence can adversely affect organ function, viability and regeneration. We have developeda mouse model of biliary senescence, based on the conditional deletion of Mdm2 in bileducts under the control of the Krt19 promoter, that exhibits features of biliary disease. Herewe report that senescent cholangiocytes induce profound alterations in the cellular andsignalling microenvironment, with recruitment of myofibroblasts and macrophages causingcollagen deposition, TGFβ production and induction of senescence in surrounding cholangiocytesand hepatocytes. Finally, we study how inhibition of TGFβ-signalling disrupts thetransmission of senescence and restores liver function. We identify cellular senescence as adetrimental mechanism in the development of biliary injury. Our results identify TGFβ as apotential therapeutic target to limit senescence-dependent aggravation in humancholangiopathies.",

keywords = "Bile ducts, Liver fibrosis, Mechanisms of disease, Senescence",

author = "Sofia Ferreira-Gonzalez and Wei-yu Lu and Alexander Raven and Benjamin Dwyer and Man, {Tak Yung} and Eoghan O{\textquoteright}Duibhir and Lewis, {Philip J. Starkey} and Lara Campana and Kendall, {Tim J.} and Bird, {Thomas G.} and Nuria Tarrats and Juan-Carlos Acosta and Luke Boulter and Forbes, {Stuart J.}",

year = "2018",

month = mar,

day = "9",

doi = "10.1038/s41467-018-03299-5",

language = "English",

volume = "9",

journal = "Nature Communications",

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TY - JOUR

T1 - Paracrine cellular senescence exacerbates biliary injury and impairs regeneration

AU - Ferreira-Gonzalez, Sofia

AU - Lu, Wei-yu

AU - Raven, Alexander

AU - Dwyer, Benjamin

AU - Man, Tak Yung

AU - O’Duibhir, Eoghan

AU - Lewis, Philip J. Starkey

AU - Campana, Lara

AU - Kendall, Tim J.

AU - Bird, Thomas G.

AU - Tarrats, Nuria

AU - Acosta, Juan-Carlos

AU - Boulter, Luke

AU - Forbes, Stuart J.

PY - 2018/3/9

Y1 - 2018/3/9

N2 - Cellular senescence is a mechanism that provides an irreversible barrier to cell cycle progressionto prevent undesired proliferation. However, under pathological circumstances,senescence can adversely affect organ function, viability and regeneration. We have developeda mouse model of biliary senescence, based on the conditional deletion of Mdm2 in bileducts under the control of the Krt19 promoter, that exhibits features of biliary disease. Herewe report that senescent cholangiocytes induce profound alterations in the cellular andsignalling microenvironment, with recruitment of myofibroblasts and macrophages causingcollagen deposition, TGFβ production and induction of senescence in surrounding cholangiocytesand hepatocytes. Finally, we study how inhibition of TGFβ-signalling disrupts thetransmission of senescence and restores liver function. We identify cellular senescence as adetrimental mechanism in the development of biliary injury. Our results identify TGFβ as apotential therapeutic target to limit senescence-dependent aggravation in humancholangiopathies.

AB - Cellular senescence is a mechanism that provides an irreversible barrier to cell cycle progressionto prevent undesired proliferation. However, under pathological circumstances,senescence can adversely affect organ function, viability and regeneration. We have developeda mouse model of biliary senescence, based on the conditional deletion of Mdm2 in bileducts under the control of the Krt19 promoter, that exhibits features of biliary disease. Herewe report that senescent cholangiocytes induce profound alterations in the cellular andsignalling microenvironment, with recruitment of myofibroblasts and macrophages causingcollagen deposition, TGFβ production and induction of senescence in surrounding cholangiocytesand hepatocytes. Finally, we study how inhibition of TGFβ-signalling disrupts thetransmission of senescence and restores liver function. We identify cellular senescence as adetrimental mechanism in the development of biliary injury. Our results identify TGFβ as apotential therapeutic target to limit senescence-dependent aggravation in humancholangiopathies.

KW - Bile ducts

KW - Liver fibrosis

KW - Mechanisms of disease

KW - Senescence

U2 - 10.1038/s41467-018-03299-5

DO - 10.1038/s41467-018-03299-5

M3 - Article

SN - 2041-1723

VL - 9

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 1020

ER -

Paracrine cellular senescence exacerbates biliary injury and impairs regeneration

Abstract / Description of output

Keywords / Materials (for Non-textual outputs)

Access to Document

Fingerprint

Projects

The Computational and Chemical Biology of the Stem Cell Niche

A HUB FOR ENGINEERING AND EXPLOITING THE STEM CELL NICHE

MRC Centre Grant Renewal

Press/Media

CRM researchers have discovered a potential new target for the treatment of a type of liver disease that affects the bile ducts.

Profiles

Juan-Carlos Acosta

Tom Bird

Luke Boulter

Cite this