Targeted Apoptosis of Ductular Reactive Cells Reduces Hepatic Fibrosis in a Mouse Model of Cholestasis
Background and Aims 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‐induci...
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Veröffentlicht in: | Hepatology (Baltimore, Md.) Md.), 2020-09, Vol.72 (3), p.1013-1028 |
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description | Background and Aims
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.
Approach and Results
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 treated with S63845 displayed a significant decrease in hepatic B lymphocytes compared to untreated mice as assessed by high‐definition mass cytometry by time‐of‐flight. Coculture of bone marrow–derived macrophages with ERCs from DKO mouse livers up‐regulated expression of the B cell–directed chemokine (C‐C motif) ligand 5. Finally, DR cells were noted to be primed for apoptosis with Bcl‐2 homologous antagonist/killer activation in vitro and in vivo in primary sclerosing cholangitis liver specimens.
Conclusions
DR cells appear to play a key role in recruiting immune cells to the liver to actively create an inflammatory and profibrogenic microenvironment. Pharmacologic targeting of MCL1 in a mouse model of chronic cholestasis reduces DR‐cell and B‐cell populations and hepatic fibrosis. |
doi_str_mv | 10.1002/hep.31211 |
format | Article |
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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.
Approach and Results
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 treated with S63845 displayed a significant decrease in hepatic B lymphocytes compared to untreated mice as assessed by high‐definition mass cytometry by time‐of‐flight. Coculture of bone marrow–derived macrophages with ERCs from DKO mouse livers up‐regulated expression of the B cell–directed chemokine (C‐C motif) ligand 5. Finally, DR cells were noted to be primed for apoptosis with Bcl‐2 homologous antagonist/killer activation in vitro and in vivo in primary sclerosing cholangitis liver specimens.
Conclusions
DR cells appear to play a key role in recruiting immune cells to the liver to actively create an inflammatory and profibrogenic microenvironment. Pharmacologic targeting of MCL1 in a mouse model of chronic cholestasis reduces DR‐cell and B‐cell populations and hepatic fibrosis.</description><identifier>ISSN: 0270-9139</identifier><identifier>EISSN: 1527-3350</identifier><identifier>DOI: 10.1002/hep.31211</identifier><identifier>PMID: 32128842</identifier><language>eng</language><publisher>United States: Wiley Subscription Services, Inc</publisher><subject>Animals ; Antineoplastic Agents - pharmacology ; Apoptosis ; Apoptosis - drug effects ; B-Lymphocytes - drug effects ; B-Lymphocytes - immunology ; Bile ; Bile Ducts, Intrahepatic - pathology ; Bone marrow ; Bone mass ; Cell adhesion & migration ; Cell adhesion molecules ; Chemokines ; Cholangitis ; Cholestasis ; Cholestasis - drug therapy ; Cholestasis - metabolism ; Cholestasis - pathology ; Cytometry ; Disease Models, Animal ; Epithelial Cell Adhesion Molecule - metabolism ; Epithelial cells ; Epithelial Cells - drug effects ; Epithelial Cells - immunology ; Fibrosis ; Gallbladder diseases ; Hepatocytes ; Hepatology ; Humans ; Inflammation ; Intravenous administration ; Ligands ; Liver ; Liver Cirrhosis - etiology ; Liver Cirrhosis - metabolism ; Liver Cirrhosis - prevention & control ; Liver diseases ; Lymphocytes B ; Macrophages ; Mcl-1 protein ; Mice ; Mice, Knockout ; Myeloid Cell Leukemia Sequence 1 Protein - antagonists & inhibitors ; Myeloid Cell Leukemia Sequence 1 Protein - metabolism ; Parenchyma ; Phenotypes ; Pyrimidines - pharmacology ; Signal Transduction - drug effects ; Thiophenes - pharmacology</subject><ispartof>Hepatology (Baltimore, Md.), 2020-09, Vol.72 (3), p.1013-1028</ispartof><rights>2020 by the American Association for the Study of Liver Diseases.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4431-938447723496cc8a8dc30bf48836dc86df87abb98815bd936db7efeae0a7e0d33</citedby><cites>FETCH-LOGICAL-c4431-938447723496cc8a8dc30bf48836dc86df87abb98815bd936db7efeae0a7e0d33</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1002%2Fhep.31211$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1002%2Fhep.31211$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>230,314,780,784,885,1417,27924,27925,45574,45575</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32128842$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Azad, Adiba I.</creatorcontrib><creatorcontrib>Krishnan, Anuradha</creatorcontrib><creatorcontrib>Troop, Leia</creatorcontrib><creatorcontrib>Li, Ying</creatorcontrib><creatorcontrib>Katsumi, Tomohiro</creatorcontrib><creatorcontrib>Pavelko, Kevin</creatorcontrib><creatorcontrib>Kostallari, Enis</creatorcontrib><creatorcontrib>Guicciardi, Maria Eugenia</creatorcontrib><creatorcontrib>Gores, Gregory J.</creatorcontrib><title>Targeted Apoptosis of Ductular Reactive Cells Reduces Hepatic Fibrosis in a Mouse Model of Cholestasis</title><title>Hepatology (Baltimore, Md.)</title><addtitle>Hepatology</addtitle><description>Background and Aims
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.
Approach and Results
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 treated with S63845 displayed a significant decrease in hepatic B lymphocytes compared to untreated mice as assessed by high‐definition mass cytometry by time‐of‐flight. Coculture of bone marrow–derived macrophages with ERCs from DKO mouse livers up‐regulated expression of the B cell–directed chemokine (C‐C motif) ligand 5. Finally, DR cells were noted to be primed for apoptosis with Bcl‐2 homologous antagonist/killer activation in vitro and in vivo in primary sclerosing cholangitis liver specimens.
Conclusions
DR cells appear to play a key role in recruiting immune cells to the liver to actively create an inflammatory and profibrogenic microenvironment. Pharmacologic targeting of MCL1 in a mouse model of chronic cholestasis reduces DR‐cell and B‐cell populations and hepatic fibrosis.</description><subject>Animals</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Apoptosis</subject><subject>Apoptosis - drug effects</subject><subject>B-Lymphocytes - drug effects</subject><subject>B-Lymphocytes - immunology</subject><subject>Bile</subject><subject>Bile Ducts, Intrahepatic - pathology</subject><subject>Bone marrow</subject><subject>Bone mass</subject><subject>Cell adhesion & migration</subject><subject>Cell adhesion molecules</subject><subject>Chemokines</subject><subject>Cholangitis</subject><subject>Cholestasis</subject><subject>Cholestasis - drug therapy</subject><subject>Cholestasis - metabolism</subject><subject>Cholestasis - pathology</subject><subject>Cytometry</subject><subject>Disease Models, Animal</subject><subject>Epithelial Cell Adhesion Molecule - metabolism</subject><subject>Epithelial cells</subject><subject>Epithelial Cells - drug effects</subject><subject>Epithelial Cells - immunology</subject><subject>Fibrosis</subject><subject>Gallbladder diseases</subject><subject>Hepatocytes</subject><subject>Hepatology</subject><subject>Humans</subject><subject>Inflammation</subject><subject>Intravenous administration</subject><subject>Ligands</subject><subject>Liver</subject><subject>Liver Cirrhosis - etiology</subject><subject>Liver Cirrhosis - metabolism</subject><subject>Liver Cirrhosis - prevention & control</subject><subject>Liver diseases</subject><subject>Lymphocytes B</subject><subject>Macrophages</subject><subject>Mcl-1 protein</subject><subject>Mice</subject><subject>Mice, Knockout</subject><subject>Myeloid Cell Leukemia Sequence 1 Protein - antagonists & inhibitors</subject><subject>Myeloid Cell Leukemia Sequence 1 Protein - metabolism</subject><subject>Parenchyma</subject><subject>Phenotypes</subject><subject>Pyrimidines - pharmacology</subject><subject>Signal Transduction - drug effects</subject><subject>Thiophenes - pharmacology</subject><issn>0270-9139</issn><issn>1527-3350</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp1kc1KJDEUhYOMaI-68AWGwGycRWn-upLaCNLqtKAoouuQSm7ZkepKmVQpvv1EW8UR3CQk98vhnByEdinZp4SwgwX0-5wyStfQhE6ZLDifkh9oQpgkRUV5tYl-pnRPCKkEUxtokzPKlBJsgpobE-9gAIeP-tAPIfmEQ4OPRzuMrYn4Gowd_CPgGbRtykc3Wkh4Dr0ZvMWnvo6vb3yHDb4IY4K8OmhfRGaL0EIaTJ5vo_XGtAl23vYtdHt6cjObF-eXf89mR-eFFYLTouJKCCkZF1VprTLKWU7qRijFS2dV6RolTV1XStFp7ap8WUtowAAxEojjfAsdrnT7sV6Cs9AN0bS6j35p4rMOxuv_J51f6LvwqKWUgpUsC-y9CcTwMGb3eumTzdlNBzmdZlxSKqayVBn9_QW9D2PscjzNhCglUaKkmfqzomz-qBSh-TBDiX5pT-f29Gt7mf312f0H-V5XBg5WwJNv4fl7JT0_uVpJ_gNCs6SE</recordid><startdate>202009</startdate><enddate>202009</enddate><creator>Azad, Adiba I.</creator><creator>Krishnan, Anuradha</creator><creator>Troop, Leia</creator><creator>Li, Ying</creator><creator>Katsumi, Tomohiro</creator><creator>Pavelko, Kevin</creator><creator>Kostallari, Enis</creator><creator>Guicciardi, Maria Eugenia</creator><creator>Gores, Gregory J.</creator><general>Wiley Subscription Services, Inc</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7T5</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>H94</scope><scope>K9.</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>202009</creationdate><title>Targeted Apoptosis of Ductular Reactive Cells Reduces Hepatic Fibrosis in a Mouse Model of Cholestasis</title><author>Azad, Adiba I. ; Krishnan, Anuradha ; Troop, Leia ; Li, Ying ; Katsumi, Tomohiro ; Pavelko, Kevin ; Kostallari, Enis ; Guicciardi, Maria Eugenia ; Gores, Gregory J.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4431-938447723496cc8a8dc30bf48836dc86df87abb98815bd936db7efeae0a7e0d33</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Animals</topic><topic>Antineoplastic Agents - pharmacology</topic><topic>Apoptosis</topic><topic>Apoptosis - drug effects</topic><topic>B-Lymphocytes - drug effects</topic><topic>B-Lymphocytes - immunology</topic><topic>Bile</topic><topic>Bile Ducts, Intrahepatic - pathology</topic><topic>Bone marrow</topic><topic>Bone mass</topic><topic>Cell adhesion & migration</topic><topic>Cell adhesion molecules</topic><topic>Chemokines</topic><topic>Cholangitis</topic><topic>Cholestasis</topic><topic>Cholestasis - drug therapy</topic><topic>Cholestasis - metabolism</topic><topic>Cholestasis - pathology</topic><topic>Cytometry</topic><topic>Disease Models, Animal</topic><topic>Epithelial Cell Adhesion Molecule - metabolism</topic><topic>Epithelial cells</topic><topic>Epithelial Cells - drug effects</topic><topic>Epithelial Cells - immunology</topic><topic>Fibrosis</topic><topic>Gallbladder diseases</topic><topic>Hepatocytes</topic><topic>Hepatology</topic><topic>Humans</topic><topic>Inflammation</topic><topic>Intravenous administration</topic><topic>Ligands</topic><topic>Liver</topic><topic>Liver Cirrhosis - etiology</topic><topic>Liver Cirrhosis - metabolism</topic><topic>Liver Cirrhosis - prevention & control</topic><topic>Liver diseases</topic><topic>Lymphocytes B</topic><topic>Macrophages</topic><topic>Mcl-1 protein</topic><topic>Mice</topic><topic>Mice, Knockout</topic><topic>Myeloid Cell Leukemia Sequence 1 Protein - antagonists & inhibitors</topic><topic>Myeloid Cell Leukemia Sequence 1 Protein - metabolism</topic><topic>Parenchyma</topic><topic>Phenotypes</topic><topic>Pyrimidines - pharmacology</topic><topic>Signal Transduction - drug effects</topic><topic>Thiophenes - pharmacology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Azad, Adiba I.</creatorcontrib><creatorcontrib>Krishnan, Anuradha</creatorcontrib><creatorcontrib>Troop, Leia</creatorcontrib><creatorcontrib>Li, Ying</creatorcontrib><creatorcontrib>Katsumi, Tomohiro</creatorcontrib><creatorcontrib>Pavelko, Kevin</creatorcontrib><creatorcontrib>Kostallari, Enis</creatorcontrib><creatorcontrib>Guicciardi, Maria Eugenia</creatorcontrib><creatorcontrib>Gores, Gregory J.</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Immunology Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Hepatology (Baltimore, Md.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Azad, Adiba I.</au><au>Krishnan, Anuradha</au><au>Troop, Leia</au><au>Li, Ying</au><au>Katsumi, Tomohiro</au><au>Pavelko, Kevin</au><au>Kostallari, Enis</au><au>Guicciardi, Maria Eugenia</au><au>Gores, Gregory J.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Targeted Apoptosis of Ductular Reactive Cells Reduces Hepatic Fibrosis in a Mouse Model of Cholestasis</atitle><jtitle>Hepatology (Baltimore, Md.)</jtitle><addtitle>Hepatology</addtitle><date>2020-09</date><risdate>2020</risdate><volume>72</volume><issue>3</issue><spage>1013</spage><epage>1028</epage><pages>1013-1028</pages><issn>0270-9139</issn><eissn>1527-3350</eissn><abstract>Background and Aims
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.
Approach and Results
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 treated with S63845 displayed a significant decrease in hepatic B lymphocytes compared to untreated mice as assessed by high‐definition mass cytometry by time‐of‐flight. Coculture of bone marrow–derived macrophages with ERCs from DKO mouse livers up‐regulated expression of the B cell–directed chemokine (C‐C motif) ligand 5. Finally, DR cells were noted to be primed for apoptosis with Bcl‐2 homologous antagonist/killer activation in vitro and in vivo in primary sclerosing cholangitis liver specimens.
Conclusions
DR cells appear to play a key role in recruiting immune cells to the liver to actively create an inflammatory and profibrogenic microenvironment. Pharmacologic targeting of MCL1 in a mouse model of chronic cholestasis reduces DR‐cell and B‐cell populations and hepatic fibrosis.</abstract><cop>United States</cop><pub>Wiley Subscription Services, Inc</pub><pmid>32128842</pmid><doi>10.1002/hep.31211</doi><tpages>16</tpages><oa>free_for_read</oa></addata></record> |
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subjects | Animals Antineoplastic Agents - pharmacology Apoptosis Apoptosis - drug effects B-Lymphocytes - drug effects B-Lymphocytes - immunology Bile Bile Ducts, Intrahepatic - pathology Bone marrow Bone mass Cell adhesion & migration Cell adhesion molecules Chemokines Cholangitis Cholestasis Cholestasis - drug therapy Cholestasis - metabolism Cholestasis - pathology Cytometry Disease Models, Animal Epithelial Cell Adhesion Molecule - metabolism Epithelial cells Epithelial Cells - drug effects Epithelial Cells - immunology Fibrosis Gallbladder diseases Hepatocytes Hepatology Humans Inflammation Intravenous administration Ligands Liver Liver Cirrhosis - etiology Liver Cirrhosis - metabolism Liver Cirrhosis - prevention & control Liver diseases Lymphocytes B Macrophages Mcl-1 protein Mice Mice, Knockout Myeloid Cell Leukemia Sequence 1 Protein - antagonists & inhibitors Myeloid Cell Leukemia Sequence 1 Protein - metabolism Parenchyma Phenotypes Pyrimidines - pharmacology Signal Transduction - drug effects Thiophenes - pharmacology |
title | Targeted Apoptosis of Ductular Reactive Cells Reduces Hepatic Fibrosis in a Mouse Model of Cholestasis |
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