Targeted Apoptosis of Ductular Reactive Cells Reduces Hepatic Fibrosis in a Mouse Model of Cholestasis.

Hepatology : Official Journal of the American Association for the Study of Liver Diseases
Adiba I AzadGregory J Gores

Abstract

In cholestatic liver diseases, ductular reactive (DR) cells extend into the hepatic parenchyma and promote inflammation and fibrosis. We have previously observed that multidrug-resistant 2 (Mdr2-/- ) double knockout (DKO) mice lacking tumor necrosis factor-related apoptosis-inducing ligand receptor (Tr-/- ) display a more extensive ductular reaction and hepatic fibrosis compared to Mdr2-/- mice. This observation suggests that the magnitude of the DR-cell population may be regulated by apoptosis. To examine this concept, we cultured epithelial cell adhesion molecule-positive reactive cholangioids (ERCs) obtained from wild-type (WT), Tr-/- , Mdr2-/- and DKO mice. Single-cell transcriptomics and immunostaining of both WT and DKO ERCs confirmed their DR-cell phenotype. Moreover, DKO ERCs displayed a unique translational cluster with expression of chemokines, indicating a reactive state. Incubation with the myeloid cell leukemia 1 (MCL1) inhibitor S63845, a proapoptotic BH3-mimetic therapy, significantly decreased DKO and Mdr2-/- ERC viability compared to WT. Intravenous administration of S63845 significantly reduced the DR-cell population and markers of inflammation and liver fibrosis in Mdr2-/- and DKO mice. Furthermore, DKO mice ...Continue Reading

References

Mar 22, 1957·Annals of the New York Academy of Sciences·C B FAVOUR
Feb 19, 2005·Science·Joseph T OpfermanStanley J Korsmeyer
Mar 29, 2005·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Andrew D CloustonJulie R Jonsson
Nov 9, 2005·The Journal of Clinical Investigation·Tatiana I NovobrantsevaAlexander Ibraghimov
Jan 24, 2007·Gastroenterology·Domenico AlvaroGianfranco Alpini
May 15, 2007·Liver International : Official Journal of the International Association for the Study of the Liver·Kumiko IsseYasuni Nakanuma
Jun 30, 2007·The American Journal of Pathology·Peter FickertMichael Trauner
Aug 1, 2008·Proceedings of the National Academy of Sciences of the United States of America·Kazuyoshi TakedaKo Okumura
Mar 13, 2010·Nature Reviews. Immunology·Frances E Lund, Troy D Randall
Apr 12, 2013·Proceedings of the National Academy of Sciences of the United States of America·Thomas G BirdStuart J Forbes
Jun 22, 2013·Genes & Development·Xi WangJoseph T Opferman
Jun 22, 2013·Genes & Development·Robert L ThomasÅsa B Gustafsson
Jun 26, 2013·Nature Reviews. Immunology·Maria-Isabel YuseffAna-Maria Lennon-Duménil
Dec 10, 2013·Gastroenterology·Michael J WilliamsStuart J Forbes
Feb 19, 2014·The Journal of Immunology : Official Journal of the American Association of Immunologists·Maude ParadisJörg H Fritz
Apr 17, 2015·Nature Communications·Amber E AlsopRuth M Kluck
May 11, 2015·Mayo Clinic Proceedings·Konstantinos N Lazaridis, Nicholas F LaRusso
Jun 13, 2015·Nature Reviews. Immunology·Ping Shen, Simon Fillatreau
Jul 21, 2015·Nature Cell Biology·Wei-Yu LuStuart J Forbes
Sep 23, 2016·The New England Journal of Medicine·Konstantinos N Lazaridis, Nicholas F LaRusso
Oct 28, 2016·Nature·András KotschyOlivier Geneste
May 21, 2017·American Journal of Physiology. Gastrointestinal and Liver Physiology·Luca FabrisMario Strazzabosco
Aug 13, 2017·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Anja MoncsekJoachim C Mertens
Aug 30, 2017·The Journal of Immunology : Official Journal of the American Association of Immunologists·Qing DingDavid M Rothstein
Sep 12, 2017·Laboratory Investigation; a Journal of Technical Methods and Pathology·Lorena LoarcaNicholas F LaRusso
Nov 4, 2017·Cell Death and Differentiation·Jerry M Adams, Suzanne Cory
Nov 7, 2017·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Francesca FaggioliBarbara Cassani
Dec 19, 2017·The American Journal of Pathology·Guido CarpinoEugenio Gaudio
Jun 9, 2018·Arthritis Research & Therapy·Estefanía Armas-GonzálezFederico Díaz-González
Aug 3, 2018·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Keisaku SatoGianfranco Alpini
Dec 19, 2018·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Carol J SorokaJames L Boyer
Jan 19, 2019·Nature Reviews. Molecular Cell Biology·Rumani SinghKristopher Sarosiek
May 21, 2019·The American Journal of Pathology·Laure-Alix ClerbauxIsabelle A Leclercq
Aug 1, 2019·American Journal of Physiology. Cell Physiology·Tomohiro KatsumiGregory J Gores
Jan 1, 2018·Cell Death and Differentiation·Jerry M Adams, Suzanne Cory
Dec 14, 2019·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Maria Eugenia GuicciardiGregory J Gores

❮ Previous
Next ❯

Citations

Aug 26, 2020·Archives of Toxicology·Ahmed Ghallab
Jan 23, 2021·Advances in Anatomic Pathology·Richa Jain, Ian Clark
Dec 24, 2020·International Journal of Molecular Sciences·Layla ShojaieLily Dara
Apr 20, 2021·JHEP Reports : Innovation in Hepatology·Mohammed AlsuraihNicholas F LaRusso
Jun 18, 2021·Advanced Drug Delivery Reviews·Alexandros Marios SofiasTwan Lammers
Jun 13, 2021·Wound Repair and Regeneration : Official Publication of the Wound Healing Society [and] the European Tissue Repair Society·Wolfgang MerktDavid Lagares

❮ Previous
Next ❯

Related Concepts

Related Feeds

Apoptosis

Apoptosis is a specific process that leads to programmed cell death through the activation of an evolutionary conserved intracellular pathway leading to pathognomic cellular changes distinct from cellular necrosis

Alagille Syndrome

Alagille syndrome is a multi-system genetic disorder that can affect the liver, heart, and other parts of the body. It’s characterization includes heart problems, liver damage, jaundice, and xanthomas. Here is the latest research.