TGFβ inhibition restores a regenerative response in acute liver injury by suppressing paracrine senescence

被引：227

作者：

Bird, Thomas G. ^{[1
,2
,3
]}

Mueller, Miryam ^{[1
]}

Boulter, Luke ^{[2
,4
]}

Vincent, David F. ^{[1
]}

Ridgway, Rachel A. ^{[1
]}

Lopez-Guadamillas, Elena ^{[5
]}

Lu, Wei-Yu ^{[2
]}

Jamieson, Thomas ^{[1
]}

Govaere, Olivier ^{[6
,7
]}

Campbell, Andrew D. ^{[1
]}

Ferreira-Gonzalez, Sofia ^{[2
]}

Cole, Alicia M. ^{[1
]}

Hay, Trevor ^{[8
]}

Simpson, Kenneth J. ^{[2
]}

Clark, William ^{[1
]}

Hedley, Ann ^{[1
]}

Clarke, Mairi ^{[9
]}

Gentaz, Pauline ^{[1
]}

Nixon, Colin ^{[1
]}

Bryce, Steven ^{[1
]}

Kiourtis, Christos ^{[1
,10
]}

Sprangers, Joep ^{[1
]}

Nibbs, Robert J. B. ^{[9
]}

Van Rooijen, Nico ^{[11
]}

Bartholin, Laurent ^{[12
]}

McGreal, Steven R. ^{[13
]}

Apte, Udayan ^{[13
]}

Barry, Simon T. ^{[14
]}

Iredale, John P. ^{[3
,15
]}

Clarke, Alan R. ^{[8
]}

Serrano, Manuel ^{[5
,16
,17
]}

Roskams, Tania A. ^{[6
,7
]}

Sansom, Owen J. ^{[1
,10
]}

Forbes, Stuart J. ^{[2
,3
]}

机构：

[1] Canc Res UK Beatson Inst, Glasgow G61 1BD, Lanark, Scotland

[2] Univ Edinburgh, MRC, Ctr Regenerat Med, 49 Little France Crescent, Edinburgh EH16 4SB, Midlothian, Scotland

[3] Univ Edinburgh, MRC, Ctr Inflammat Res, Queens Med Res Inst, 49 Little France Crescent, Edinburgh EH16 4TJ, Midlothian, Scotland

[4] Inst Genet & Mol Med, MRC Human Genet Unit, Edinburgh EH4 2XU, Midlothian, Scotland

[5] Spanish Natl Canc Res Ctr CNIO, Tumor Suppress Grp, Madrid 28029, Spain

[6] Katholieke Univ Leuven, Dept Imaging & Pathol, B-3000 Leuven, Belgium

[7] Univ Hosp Leuven, B-3000 Leuven, Belgium

[8] Cardiff Univ, Sch Biosci, Cardiff CF10 3AX, S Glam, Wales

[9] Univ Glasgow, Coll Med Vet & Life Sci, Inst Infect Immun & Inflammat, Glasgow G12 8TA, Lanark, Scotland

[10] Univ Glasgow, Inst Canc Sci, Glasgow G61 1QH, Lanark, Scotland

[11] Vrije Univ, Med Ctr, Dept Mol Cell Biol, Van der Boechorststr 7, NL-1081 BT Amsterdam, Netherlands

[12] Lyon I Univ, Ctr Rech Cancerol Lyon, UMR INSERM 1052, UMR S 1052,CNRS 5286, F-69373 Lyon 08, France

[13] Univ Kansas, Dept Pharmacol Toxicol & Therapeut, Med Ctr, Kansas City, KS 66160 USA

[14] AstraZeneca, Oncol, IMED Biotech Unit, Cambridge CB2 0AA, England

[15] Univ Bristol, Senate House,Tyndall Ave, Bristol BS8 1TH, Avon, England

[16] Barcelona Inst Sci & Technol, Inst Res Biomed IRB Barcelona, Barcelona, Spain

[17] Catalan Inst Res & Adv Studies, Barcelona, Spain

来源：

SCIENCE TRANSLATIONAL MEDICINE | 2018年 / 10卷 / 454期

基金：

英国惠康基金; 英国医学研究理事会;

关键词：

GROWTH-FACTOR-BETA; CELLS; MICE; HEPATOCYTES; INFLAMMATION; MACROPHAGES; EXPRESSION; INDUCTION; DETECT; DRIVEN;

D O I：

10.1126/scitranslmed.aan1230

中图分类号：

Q2 [细胞生物学];

学科分类号：

071013 [干细胞生物学];

摘要：

Liver injury results in rapid regeneration through hepatocyte proliferation and hypertrophy. However, after acute severe injury, such as acetaminophen poisoning, effective regeneration may fail. We investigated how senescence may underlie this regenerative failure. In human acute liver disease, and murine models, p21-dependent hepatocellular senescence was proportionate to disease severity and was associated with impaired regeneration. In an acetaminophen injury mouse model, a transcriptional signature associated with the induction of paracrine senescence was observed within 24 hours and was followed by one of impaired proliferation. In mouse genetic models of hepatocyte injury and senescence, we observed transmission of senescence to local uninjured hepatocytes. Spread of senescence depended on macrophage-derived transforming growth factor-beta 1 (TGF beta 1) ligand. In acetaminophen poisoning, inhibition of TGF beta receptor 1 (TGF beta R1) improved mouse survival.TGF beta R1 inhibition reduced senescence and enhanced liver regeneration even when delivered beyond the therapeutic window for treating acetaminophen poisoning. This mechanism, in which injury-induced senescence impairs liver regeneration, is an attractive therapeutic target for developing treatments for acute liver failure.

引用

页数：14

共 62 条

[1]

A complex secretory program orchestrated by the inflammasome controls paracrine senescence [J].

Acosta, Juan Carlos ;

Banito, Ana ;

Wuestefeld, Torsten ;

Georgilis, Athena ;

Janich, Peggy ;

Morton, Jennifer P. ;

Athineos, Dimitris ;

Kang, Tae-Won ;

Lasitschka, Felix ;

Andrulis, Mindaugas ;

Pascual, Gloria ;

Morris, Kelly J. ;

Khan, Sadaf ;

Jin, Hong ;

Dharmalingam, Gopuraja ;

Snijders, Ambrosius P. ;

Carroll, Thomas ;

Capper, David ;

Pritchard, Catrin ;

Inman, Gareth J. ;

Longerich, Thomas ;

Sansom, Owen J. ;

Aznar Benitah, Salvador ;

Zender, Lars ;

Gil, Jesus .

NATURE CELL BIOLOGY, 2013, 15 (08) :978-U221

[2]

Induction of Heart Valve Lesions by Small-Molecule ALK5 Inhibitors [J].

Anderton, Mark J. ;

Mellor, Howard R. ;

Bell, Alex ;

Sadler, Claire ;

Pass, Martin ;

Powell, Steve ;

Steele, Samantha J. ;

Roberts, Ruth. R. A. ;

Heier, Annabelle .

TOXICOLOGIC PATHOLOGY, 2011, 39 (06) :916-924

[3]

Source and characterization of hepatic macrophages in acetaminophen-induced acute liver failure in humans [J].

Antoniades, Charalambos Gustav ;

Quaglia, Alberto ;

Taams, Leonie S. ;

Mitry, Ragai R. ;

Hussain, Munther ;

Abeles, Robin ;

Possamai, Lucia A. ;

Bruce, Matthew ;

McPhail, Mark ;

Starling, Christopher ;

Wagner, Bart ;

Barnardo, Adrian ;

Pomplun, Sabine ;

Auzinger, Georg ;

Bernal, William ;

Heaton, Nigel ;

Vergani, Diego ;

Thursz, Mark R. ;

Wendon, Julia .

HEPATOLOGY, 2012, 56 (02) :735-746

[4]

Senescence in chronic liver disease: Is the future in aging? [J].

Arayinthan, Aloysious D. ;

Alexander, Graeme J. M. .

JOURNAL OF HEPATOLOGY, 2016, 65 (04) :825-834

[5]

Generation of Mice with Conditionally Activated Transforming Growth Factor Beta Signaling Through the TβRI/ALK5 Receptor [J].

Bartholin, Laurent ;

Cyprian, Farhan S. ;

Vincent, David ;

Garcia, Celine N. ;

Martel, Sylvie ;

Horvat, Branka ;

Berthet, Cyril ;

Goddard-Leon, Sophie ;

Treilleux, Isabelle ;

Rimokh, Ruth ;

Marie, Julien C. .

GENESIS, 2008, 46 (12) :724-731

[6]

Acute Liver Failure [J].

Bernal, William ;

Wendon, Julia .

NEW ENGLAND JOURNAL OF MEDICINE, 2013, 369 (26) :2525-2534

[7]

TGFβ inhibition restores a regenerative response in acute liver injury by suppressing paracrine senescence [J].

Bird, Thomas G. ;

Mueller, Miryam ;

Boulter, Luke ;

Vincent, David F. ;

Ridgway, Rachel A. ;

Lopez-Guadamillas, Elena ;

Lu, Wei-Yu ;

Jamieson, Thomas ;

Govaere, Olivier ;

Campbell, Andrew D. ;

Ferreira-Gonzalez, Sofia ;

Cole, Alicia M. ;

Hay, Trevor ;

Simpson, Kenneth J. ;

Clark, William ;

Hedley, Ann ;

Clarke, Mairi ;

Gentaz, Pauline ;

Nixon, Colin ;

Bryce, Steven ;

Kiourtis, Christos ;

Sprangers, Joep ;

Nibbs, Robert J. B. ;

Van Rooijen, Nico ;

Bartholin, Laurent ;

McGreal, Steven R. ;

Apte, Udayan ;

Barry, Simon T. ;

Iredale, John P. ;

Clarke, Alan R. ;

Serrano, Manuel ;

Roskams, Tania A. ;

Sansom, Owen J. ;

Forbes, Stuart J. .

SCIENCE TRANSLATIONAL MEDICINE, 2018, 10 (454)

[8]

Macrophage-derived Wnt opposes Notch signaling to specify hepatic progenitor cell fate in chronic liver disease [J].

Boulter, Luke ;

Govaere, Olivier ;

Bird, Tom G. ;

Radulescu, Sorina ;

Ramachandran, Prakash ;

Pellicoro, Antonella ;

Ridgway, Rachel A. ;

Seo, Sang Soo ;

Spee, Bart ;

Van Rooijen, Nico ;

Sansom, Owen J. ;

Iredale, John P. ;

Lowell, Sally ;

Roskams, Tania ;

Forbes, Stuart J. .

NATURE MEDICINE, 2012, 18 (04) :572-579

[9]

Modernizing Reference Genome Assemblies [J].

Church, Deanna M. ;

Schneider, Valerie A. ;

Graves, Tina ;

Auger, Katherine ;

Cunningham, Fiona ;

Bouk, Nathan ;

Chen, Hsiu-Chuan ;

Agarwala, Richa ;

McLaren, William M. ;

Ritchie, Graham R. S. ;

Albracht, Derek ;

Kremitzki, Milinn ;

Rock, Susan ;

Kotkiewicz, Holland ;

Kremitzki, Colin ;

Wollam, Aye ;

Trani, Lee ;

Fulton, Lucinda ;

Fulton, Robert ;

Matthews, Lucy ;

Whitehead, Siobhan ;

Chow, Will ;

Torrance, James ;

Dunn, Matthew ;

Harden, Glenn ;

Threadgold, Glen ;

Wood, Jonathan ;

Collins, Joanna ;

Heath, Paul ;

Griffiths, Guy ;

Pelan, Sarah ;

Grafham, Darren ;

Eichler, Evan E. ;

Weinstock, George ;

Mardis, Elaine R. ;

Wilson, Richard K. ;

Howe, Kerstin ;

Flicek, Paul ;

Hubbard, Tim .

PLOS BIOLOGY, 2011, 9 (07)

[10]

p21 loss blocks senescence following Apc loss and provokes tumourigenesis in the renal but not the intestinal epithelium [J].

Cole, Alicia M. ;

Ridgway, Rachel A. ;

Derkits, Sahra E. ;

Parry, Lee ;

Barker, Nick ;

Clevers, Hans ;

Clarke, Alan R. ;

Sansom, Owen J. .

EMBO MOLECULAR MEDICINE, 2010, 2 (11) :472-486

← 1 2 3 4 5 6 7 →