Loading…
Liver stromal cells restrict macrophage maturation and stromal IL-6 limits the differentiation of cirrhosis-linked macrophages
Myeloid cells are key regulators of cirrhosis, a major cause of mortality worldwide. Because stromal cells can modulate the functionality of myeloid cells in vitro, targeting stromal-myeloid interactions has become an attractive potential therapeutic strategy. We aimed to investigate how human liver...
Saved in:
Published in: | Journal of hepatology 2022-05, Vol.76 (5), p.1127-1137 |
---|---|
Main Authors: | , , , , , , , , , , , , |
Format: | Article |
Language: | English |
Subjects: | |
Citations: | Items that this one cites Items that cite this one |
Online Access: | Get full text |
Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
cited_by | cdi_FETCH-LOGICAL-c472t-b774c98c52c78fb2c7f3b9274dd355182bf1aa61cdc9612ffd7028968b11f5d63 |
---|---|
cites | cdi_FETCH-LOGICAL-c472t-b774c98c52c78fb2c7f3b9274dd355182bf1aa61cdc9612ffd7028968b11f5d63 |
container_end_page | 1137 |
container_issue | 5 |
container_start_page | 1127 |
container_title | Journal of hepatology |
container_volume | 76 |
creator | Buonomo, Erica L. Mei, Shenglin Guinn, Samantha R. Leo, Isabelle R. Peluso, Michael J. Nolan, Mei-An Schildberg, Frank A. Zhao, Lei Lian, Christine Xu, Shuyun Misdraji, Joseph Kharchenko, Peter V. Sharpe, Arlene H. |
description | Myeloid cells are key regulators of cirrhosis, a major cause of mortality worldwide. Because stromal cells can modulate the functionality of myeloid cells in vitro, targeting stromal-myeloid interactions has become an attractive potential therapeutic strategy. We aimed to investigate how human liver stromal cells impact myeloid cell properties and to understand the utility of a stromal-myeloid coculture system to study these interactions in the context of cirrhosis.
Single-cell RNA-sequencing analyses of non-cirrhotic (n = 7) and cirrhotic (n = 5) human liver tissue were correlated to the bulk RNA-sequencing results of in vitro cocultured human CD14+ and primary liver stromal cells. Complimentary mechanistic experiments and flow cytometric analysis were performed on human liver stromal-myeloid coculture systems.
We found that stromal-myeloid coculture reduces the frequency CD14+ cell subsets transcriptionally similar to liver macrophages, showing that stromal cells inhibit the maturation of monocytes into macrophages. Stromal cells also influenced in vitro macrophage differentiation by skewing away from cirrhosis-linked CD9+ scar-associated macrophage-like cells and towards CD163+ Kupffer cell-like macrophages. We identify IL-6 production as a mechanism by which stromal cells limit CD9+ macrophage differentiation and find that local IL-6 levels are decreased in early-stage human liver disease compared to healthy liver tissue, suggesting a protective role for local IL-6 in the healthy liver.
Our work reveals an unanticipated role for liver stromal cells in impeding the maturation and altering the differentiation of macrophages and should prompt investigations into the role of local IL-6 production in the pathogenesis of liver disease. These studies provide a framework for investigating macrophage-stromal interactions during cirrhosis.
The impact of human liver stromal cells on myeloid cell maturation and differentiation in liver disease is incompletely understood. In this study, we present a mechanistic analysis using a primary in vitro human liver stromal-myeloid coculture system that is translated to liver disease using single-cell RNA sequencing analysis of cirrhotic and non-cirrhotic human liver tissue. Our work supports a role for stromal cell contact in restricting macrophage maturation and for stromal-derived IL-6 in limiting the differentiation of a cirrhotic macrophage subset.
[Display omitted]
•Translated in vitro human stromal-myeloid interaction |
doi_str_mv | 10.1016/j.jhep.2021.12.036 |
format | article |
fullrecord | <record><control><sourceid>proquest_swepu</sourceid><recordid>TN_cdi_swepub_primary_oai_swepub_ki_se_455998</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><els_id>S0168827822000071</els_id><sourcerecordid>2622657582</sourcerecordid><originalsourceid>FETCH-LOGICAL-c472t-b774c98c52c78fb2c7f3b9274dd355182bf1aa61cdc9612ffd7028968b11f5d63</originalsourceid><addsrcrecordid>eNp9kk2L1TAYhYsozp3RP-BCCm7c9JqkzRe4kUGdgQtudB3S5I03nbapSTvixt9uSu9cRdBNvnjOITk5RfECoz1GmL3p9t0Rpj1BBO8x2aOaPSp2mCFUIdbgx8UuQ6IShIuL4jKlDiFUI9k8LS5qinjT8GZX_Dz4e4hlmmMYdF8a6PtURsh7b-Zy0CaG6ai_Ql7OS9SzD2OpR3sW3B4qVvZ-8HMq5yOU1jsHEcbZb2xwpfExHkPyqer9eAf2D9f0rHjidJ_g-Wm-Kr58eP_5-qY6fPp4e_3uUJmGk7lqOW-MFIYSw4Vr8-jqVhLeWFtTigVpHdaaYWONZJg4ZzkiQjLRYuyoZfVVUW2-6TtMS6um6Acdf6igvTod3eUVqIZSKUXm5T_5KQb7W_QgxBRhWSOCsvb1ps3gtyVHqQaf1mD1CGFJijBCGOVUkIy--gvtwhLHnESm5PoyIVdDslE5tpQiuPN1MFJrE1Sn1iaotQkKE5WbkEUvT9ZLO4A9Sx6-PgNvNwBy7vceokrGw2jA-ghmVjb4__n_At9Xx7Y</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2695518890</pqid></control><display><type>article</type><title>Liver stromal cells restrict macrophage maturation and stromal IL-6 limits the differentiation of cirrhosis-linked macrophages</title><source>ScienceDirect Freedom Collection</source><creator>Buonomo, Erica L. ; Mei, Shenglin ; Guinn, Samantha R. ; Leo, Isabelle R. ; Peluso, Michael J. ; Nolan, Mei-An ; Schildberg, Frank A. ; Zhao, Lei ; Lian, Christine ; Xu, Shuyun ; Misdraji, Joseph ; Kharchenko, Peter V. ; Sharpe, Arlene H.</creator><creatorcontrib>Buonomo, Erica L. ; Mei, Shenglin ; Guinn, Samantha R. ; Leo, Isabelle R. ; Peluso, Michael J. ; Nolan, Mei-An ; Schildberg, Frank A. ; Zhao, Lei ; Lian, Christine ; Xu, Shuyun ; Misdraji, Joseph ; Kharchenko, Peter V. ; Sharpe, Arlene H.</creatorcontrib><description>Myeloid cells are key regulators of cirrhosis, a major cause of mortality worldwide. Because stromal cells can modulate the functionality of myeloid cells in vitro, targeting stromal-myeloid interactions has become an attractive potential therapeutic strategy. We aimed to investigate how human liver stromal cells impact myeloid cell properties and to understand the utility of a stromal-myeloid coculture system to study these interactions in the context of cirrhosis.
Single-cell RNA-sequencing analyses of non-cirrhotic (n = 7) and cirrhotic (n = 5) human liver tissue were correlated to the bulk RNA-sequencing results of in vitro cocultured human CD14+ and primary liver stromal cells. Complimentary mechanistic experiments and flow cytometric analysis were performed on human liver stromal-myeloid coculture systems.
We found that stromal-myeloid coculture reduces the frequency CD14+ cell subsets transcriptionally similar to liver macrophages, showing that stromal cells inhibit the maturation of monocytes into macrophages. Stromal cells also influenced in vitro macrophage differentiation by skewing away from cirrhosis-linked CD9+ scar-associated macrophage-like cells and towards CD163+ Kupffer cell-like macrophages. We identify IL-6 production as a mechanism by which stromal cells limit CD9+ macrophage differentiation and find that local IL-6 levels are decreased in early-stage human liver disease compared to healthy liver tissue, suggesting a protective role for local IL-6 in the healthy liver.
Our work reveals an unanticipated role for liver stromal cells in impeding the maturation and altering the differentiation of macrophages and should prompt investigations into the role of local IL-6 production in the pathogenesis of liver disease. These studies provide a framework for investigating macrophage-stromal interactions during cirrhosis.
The impact of human liver stromal cells on myeloid cell maturation and differentiation in liver disease is incompletely understood. In this study, we present a mechanistic analysis using a primary in vitro human liver stromal-myeloid coculture system that is translated to liver disease using single-cell RNA sequencing analysis of cirrhotic and non-cirrhotic human liver tissue. Our work supports a role for stromal cell contact in restricting macrophage maturation and for stromal-derived IL-6 in limiting the differentiation of a cirrhotic macrophage subset.
[Display omitted]
•Translated in vitro human stromal-myeloid interactions to cells in human cirrhosis.•Stromal cells limit the transition of CD14+ monocytes into HLA-DRhi macrophages.•Stromal cell-secreted IL-6 limits the macrophage differentiation into CD9+ cirrhotic macrophages.•Local IL-6 levels are decreased in early-stage human liver disease.</description><identifier>ISSN: 0168-8278</identifier><identifier>ISSN: 1600-0641</identifier><identifier>EISSN: 1600-0641</identifier><identifier>DOI: 10.1016/j.jhep.2021.12.036</identifier><identifier>PMID: 35074474</identifier><language>eng</language><publisher>Netherlands: Elsevier B.V</publisher><subject>CD14 antigen ; CD163 antigen ; CD9 antigen ; Cell Differentiation ; Cirrhosis ; Flow cytometry ; Hepatocytes ; human ; Humans ; IL-6 ; Interleukin 6 ; liver ; Liver cirrhosis ; Liver Cirrhosis - etiology ; Liver diseases ; Liver Diseases - pathology ; macrophage differentiation ; macrophage maturation ; Macrophages ; Macrophages - pathology ; Medicin och hälsovetenskap ; Monocytes ; Monocytes - pathology ; Myeloid cells ; Ribonucleic acid ; RNA ; Sequence analysis ; single-cell RNA-seq ; Stromal cells ; Stromal Cells - pathology</subject><ispartof>Journal of hepatology, 2022-05, Vol.76 (5), p.1127-1137</ispartof><rights>2022 European Association for the Study of the Liver</rights><rights>Copyright © 2022 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.</rights><rights>Copyright Elsevier Science Ltd. May 2022</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c472t-b774c98c52c78fb2c7f3b9274dd355182bf1aa61cdc9612ffd7028968b11f5d63</citedby><cites>FETCH-LOGICAL-c472t-b774c98c52c78fb2c7f3b9274dd355182bf1aa61cdc9612ffd7028968b11f5d63</cites><orcidid>0000-0002-7627-6690 ; 0000-0003-4322-6475 ; 0000-0002-9529-048X ; 0000-0002-4558-8915 ; 0000-0003-0797-1945 ; 0000-0003-4626-1612 ; 0000-0002-8109-7339 ; 0000-0003-2762-4772</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,780,784,885,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/35074474$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttp://kipublications.ki.se/Default.aspx?queryparsed=id:150193020$$DView record from Swedish Publication Index$$Hfree_for_read</backlink></links><search><creatorcontrib>Buonomo, Erica L.</creatorcontrib><creatorcontrib>Mei, Shenglin</creatorcontrib><creatorcontrib>Guinn, Samantha R.</creatorcontrib><creatorcontrib>Leo, Isabelle R.</creatorcontrib><creatorcontrib>Peluso, Michael J.</creatorcontrib><creatorcontrib>Nolan, Mei-An</creatorcontrib><creatorcontrib>Schildberg, Frank A.</creatorcontrib><creatorcontrib>Zhao, Lei</creatorcontrib><creatorcontrib>Lian, Christine</creatorcontrib><creatorcontrib>Xu, Shuyun</creatorcontrib><creatorcontrib>Misdraji, Joseph</creatorcontrib><creatorcontrib>Kharchenko, Peter V.</creatorcontrib><creatorcontrib>Sharpe, Arlene H.</creatorcontrib><title>Liver stromal cells restrict macrophage maturation and stromal IL-6 limits the differentiation of cirrhosis-linked macrophages</title><title>Journal of hepatology</title><addtitle>J Hepatol</addtitle><description>Myeloid cells are key regulators of cirrhosis, a major cause of mortality worldwide. Because stromal cells can modulate the functionality of myeloid cells in vitro, targeting stromal-myeloid interactions has become an attractive potential therapeutic strategy. We aimed to investigate how human liver stromal cells impact myeloid cell properties and to understand the utility of a stromal-myeloid coculture system to study these interactions in the context of cirrhosis.
Single-cell RNA-sequencing analyses of non-cirrhotic (n = 7) and cirrhotic (n = 5) human liver tissue were correlated to the bulk RNA-sequencing results of in vitro cocultured human CD14+ and primary liver stromal cells. Complimentary mechanistic experiments and flow cytometric analysis were performed on human liver stromal-myeloid coculture systems.
We found that stromal-myeloid coculture reduces the frequency CD14+ cell subsets transcriptionally similar to liver macrophages, showing that stromal cells inhibit the maturation of monocytes into macrophages. Stromal cells also influenced in vitro macrophage differentiation by skewing away from cirrhosis-linked CD9+ scar-associated macrophage-like cells and towards CD163+ Kupffer cell-like macrophages. We identify IL-6 production as a mechanism by which stromal cells limit CD9+ macrophage differentiation and find that local IL-6 levels are decreased in early-stage human liver disease compared to healthy liver tissue, suggesting a protective role for local IL-6 in the healthy liver.
Our work reveals an unanticipated role for liver stromal cells in impeding the maturation and altering the differentiation of macrophages and should prompt investigations into the role of local IL-6 production in the pathogenesis of liver disease. These studies provide a framework for investigating macrophage-stromal interactions during cirrhosis.
The impact of human liver stromal cells on myeloid cell maturation and differentiation in liver disease is incompletely understood. In this study, we present a mechanistic analysis using a primary in vitro human liver stromal-myeloid coculture system that is translated to liver disease using single-cell RNA sequencing analysis of cirrhotic and non-cirrhotic human liver tissue. Our work supports a role for stromal cell contact in restricting macrophage maturation and for stromal-derived IL-6 in limiting the differentiation of a cirrhotic macrophage subset.
[Display omitted]
•Translated in vitro human stromal-myeloid interactions to cells in human cirrhosis.•Stromal cells limit the transition of CD14+ monocytes into HLA-DRhi macrophages.•Stromal cell-secreted IL-6 limits the macrophage differentiation into CD9+ cirrhotic macrophages.•Local IL-6 levels are decreased in early-stage human liver disease.</description><subject>CD14 antigen</subject><subject>CD163 antigen</subject><subject>CD9 antigen</subject><subject>Cell Differentiation</subject><subject>Cirrhosis</subject><subject>Flow cytometry</subject><subject>Hepatocytes</subject><subject>human</subject><subject>Humans</subject><subject>IL-6</subject><subject>Interleukin 6</subject><subject>liver</subject><subject>Liver cirrhosis</subject><subject>Liver Cirrhosis - etiology</subject><subject>Liver diseases</subject><subject>Liver Diseases - pathology</subject><subject>macrophage differentiation</subject><subject>macrophage maturation</subject><subject>Macrophages</subject><subject>Macrophages - pathology</subject><subject>Medicin och hälsovetenskap</subject><subject>Monocytes</subject><subject>Monocytes - pathology</subject><subject>Myeloid cells</subject><subject>Ribonucleic acid</subject><subject>RNA</subject><subject>Sequence analysis</subject><subject>single-cell RNA-seq</subject><subject>Stromal cells</subject><subject>Stromal Cells - pathology</subject><issn>0168-8278</issn><issn>1600-0641</issn><issn>1600-0641</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2022</creationdate><recordtype>article</recordtype><recordid>eNp9kk2L1TAYhYsozp3RP-BCCm7c9JqkzRe4kUGdgQtudB3S5I03nbapSTvixt9uSu9cRdBNvnjOITk5RfECoz1GmL3p9t0Rpj1BBO8x2aOaPSp2mCFUIdbgx8UuQ6IShIuL4jKlDiFUI9k8LS5qinjT8GZX_Dz4e4hlmmMYdF8a6PtURsh7b-Zy0CaG6ai_Ql7OS9SzD2OpR3sW3B4qVvZ-8HMq5yOU1jsHEcbZb2xwpfExHkPyqer9eAf2D9f0rHjidJ_g-Wm-Kr58eP_5-qY6fPp4e_3uUJmGk7lqOW-MFIYSw4Vr8-jqVhLeWFtTigVpHdaaYWONZJg4ZzkiQjLRYuyoZfVVUW2-6TtMS6um6Acdf6igvTod3eUVqIZSKUXm5T_5KQb7W_QgxBRhWSOCsvb1ps3gtyVHqQaf1mD1CGFJijBCGOVUkIy--gvtwhLHnESm5PoyIVdDslE5tpQiuPN1MFJrE1Sn1iaotQkKE5WbkEUvT9ZLO4A9Sx6-PgNvNwBy7vceokrGw2jA-ghmVjb4__n_At9Xx7Y</recordid><startdate>20220501</startdate><enddate>20220501</enddate><creator>Buonomo, Erica L.</creator><creator>Mei, Shenglin</creator><creator>Guinn, Samantha R.</creator><creator>Leo, Isabelle R.</creator><creator>Peluso, Michael J.</creator><creator>Nolan, Mei-An</creator><creator>Schildberg, Frank A.</creator><creator>Zhao, Lei</creator><creator>Lian, Christine</creator><creator>Xu, Shuyun</creator><creator>Misdraji, Joseph</creator><creator>Kharchenko, Peter V.</creator><creator>Sharpe, Arlene H.</creator><general>Elsevier B.V</general><general>Elsevier Science Ltd</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>H94</scope><scope>7X8</scope><scope>ADTPV</scope><scope>AOWAS</scope><orcidid>https://orcid.org/0000-0002-7627-6690</orcidid><orcidid>https://orcid.org/0000-0003-4322-6475</orcidid><orcidid>https://orcid.org/0000-0002-9529-048X</orcidid><orcidid>https://orcid.org/0000-0002-4558-8915</orcidid><orcidid>https://orcid.org/0000-0003-0797-1945</orcidid><orcidid>https://orcid.org/0000-0003-4626-1612</orcidid><orcidid>https://orcid.org/0000-0002-8109-7339</orcidid><orcidid>https://orcid.org/0000-0003-2762-4772</orcidid></search><sort><creationdate>20220501</creationdate><title>Liver stromal cells restrict macrophage maturation and stromal IL-6 limits the differentiation of cirrhosis-linked macrophages</title><author>Buonomo, Erica L. ; Mei, Shenglin ; Guinn, Samantha R. ; Leo, Isabelle R. ; Peluso, Michael J. ; Nolan, Mei-An ; Schildberg, Frank A. ; Zhao, Lei ; Lian, Christine ; Xu, Shuyun ; Misdraji, Joseph ; Kharchenko, Peter V. ; Sharpe, Arlene H.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c472t-b774c98c52c78fb2c7f3b9274dd355182bf1aa61cdc9612ffd7028968b11f5d63</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2022</creationdate><topic>CD14 antigen</topic><topic>CD163 antigen</topic><topic>CD9 antigen</topic><topic>Cell Differentiation</topic><topic>Cirrhosis</topic><topic>Flow cytometry</topic><topic>Hepatocytes</topic><topic>human</topic><topic>Humans</topic><topic>IL-6</topic><topic>Interleukin 6</topic><topic>liver</topic><topic>Liver cirrhosis</topic><topic>Liver Cirrhosis - etiology</topic><topic>Liver diseases</topic><topic>Liver Diseases - pathology</topic><topic>macrophage differentiation</topic><topic>macrophage maturation</topic><topic>Macrophages</topic><topic>Macrophages - pathology</topic><topic>Medicin och hälsovetenskap</topic><topic>Monocytes</topic><topic>Monocytes - pathology</topic><topic>Myeloid cells</topic><topic>Ribonucleic acid</topic><topic>RNA</topic><topic>Sequence analysis</topic><topic>single-cell RNA-seq</topic><topic>Stromal cells</topic><topic>Stromal Cells - pathology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Buonomo, Erica L.</creatorcontrib><creatorcontrib>Mei, Shenglin</creatorcontrib><creatorcontrib>Guinn, Samantha R.</creatorcontrib><creatorcontrib>Leo, Isabelle R.</creatorcontrib><creatorcontrib>Peluso, Michael J.</creatorcontrib><creatorcontrib>Nolan, Mei-An</creatorcontrib><creatorcontrib>Schildberg, Frank A.</creatorcontrib><creatorcontrib>Zhao, Lei</creatorcontrib><creatorcontrib>Lian, Christine</creatorcontrib><creatorcontrib>Xu, Shuyun</creatorcontrib><creatorcontrib>Misdraji, Joseph</creatorcontrib><creatorcontrib>Kharchenko, Peter V.</creatorcontrib><creatorcontrib>Sharpe, Arlene H.</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>AIDS and Cancer Research Abstracts</collection><collection>MEDLINE - Academic</collection><collection>SwePub</collection><collection>SwePub Articles</collection><jtitle>Journal of hepatology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Buonomo, Erica L.</au><au>Mei, Shenglin</au><au>Guinn, Samantha R.</au><au>Leo, Isabelle R.</au><au>Peluso, Michael J.</au><au>Nolan, Mei-An</au><au>Schildberg, Frank A.</au><au>Zhao, Lei</au><au>Lian, Christine</au><au>Xu, Shuyun</au><au>Misdraji, Joseph</au><au>Kharchenko, Peter V.</au><au>Sharpe, Arlene H.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Liver stromal cells restrict macrophage maturation and stromal IL-6 limits the differentiation of cirrhosis-linked macrophages</atitle><jtitle>Journal of hepatology</jtitle><addtitle>J Hepatol</addtitle><date>2022-05-01</date><risdate>2022</risdate><volume>76</volume><issue>5</issue><spage>1127</spage><epage>1137</epage><pages>1127-1137</pages><issn>0168-8278</issn><issn>1600-0641</issn><eissn>1600-0641</eissn><abstract>Myeloid cells are key regulators of cirrhosis, a major cause of mortality worldwide. Because stromal cells can modulate the functionality of myeloid cells in vitro, targeting stromal-myeloid interactions has become an attractive potential therapeutic strategy. We aimed to investigate how human liver stromal cells impact myeloid cell properties and to understand the utility of a stromal-myeloid coculture system to study these interactions in the context of cirrhosis.
Single-cell RNA-sequencing analyses of non-cirrhotic (n = 7) and cirrhotic (n = 5) human liver tissue were correlated to the bulk RNA-sequencing results of in vitro cocultured human CD14+ and primary liver stromal cells. Complimentary mechanistic experiments and flow cytometric analysis were performed on human liver stromal-myeloid coculture systems.
We found that stromal-myeloid coculture reduces the frequency CD14+ cell subsets transcriptionally similar to liver macrophages, showing that stromal cells inhibit the maturation of monocytes into macrophages. Stromal cells also influenced in vitro macrophage differentiation by skewing away from cirrhosis-linked CD9+ scar-associated macrophage-like cells and towards CD163+ Kupffer cell-like macrophages. We identify IL-6 production as a mechanism by which stromal cells limit CD9+ macrophage differentiation and find that local IL-6 levels are decreased in early-stage human liver disease compared to healthy liver tissue, suggesting a protective role for local IL-6 in the healthy liver.
Our work reveals an unanticipated role for liver stromal cells in impeding the maturation and altering the differentiation of macrophages and should prompt investigations into the role of local IL-6 production in the pathogenesis of liver disease. These studies provide a framework for investigating macrophage-stromal interactions during cirrhosis.
The impact of human liver stromal cells on myeloid cell maturation and differentiation in liver disease is incompletely understood. In this study, we present a mechanistic analysis using a primary in vitro human liver stromal-myeloid coculture system that is translated to liver disease using single-cell RNA sequencing analysis of cirrhotic and non-cirrhotic human liver tissue. Our work supports a role for stromal cell contact in restricting macrophage maturation and for stromal-derived IL-6 in limiting the differentiation of a cirrhotic macrophage subset.
[Display omitted]
•Translated in vitro human stromal-myeloid interactions to cells in human cirrhosis.•Stromal cells limit the transition of CD14+ monocytes into HLA-DRhi macrophages.•Stromal cell-secreted IL-6 limits the macrophage differentiation into CD9+ cirrhotic macrophages.•Local IL-6 levels are decreased in early-stage human liver disease.</abstract><cop>Netherlands</cop><pub>Elsevier B.V</pub><pmid>35074474</pmid><doi>10.1016/j.jhep.2021.12.036</doi><tpages>11</tpages><orcidid>https://orcid.org/0000-0002-7627-6690</orcidid><orcidid>https://orcid.org/0000-0003-4322-6475</orcidid><orcidid>https://orcid.org/0000-0002-9529-048X</orcidid><orcidid>https://orcid.org/0000-0002-4558-8915</orcidid><orcidid>https://orcid.org/0000-0003-0797-1945</orcidid><orcidid>https://orcid.org/0000-0003-4626-1612</orcidid><orcidid>https://orcid.org/0000-0002-8109-7339</orcidid><orcidid>https://orcid.org/0000-0003-2762-4772</orcidid></addata></record> |
fulltext | fulltext |
identifier | ISSN: 0168-8278 |
ispartof | Journal of hepatology, 2022-05, Vol.76 (5), p.1127-1137 |
issn | 0168-8278 1600-0641 1600-0641 |
language | eng |
recordid | cdi_swepub_primary_oai_swepub_ki_se_455998 |
source | ScienceDirect Freedom Collection |
subjects | CD14 antigen CD163 antigen CD9 antigen Cell Differentiation Cirrhosis Flow cytometry Hepatocytes human Humans IL-6 Interleukin 6 liver Liver cirrhosis Liver Cirrhosis - etiology Liver diseases Liver Diseases - pathology macrophage differentiation macrophage maturation Macrophages Macrophages - pathology Medicin och hälsovetenskap Monocytes Monocytes - pathology Myeloid cells Ribonucleic acid RNA Sequence analysis single-cell RNA-seq Stromal cells Stromal Cells - pathology |
title | Liver stromal cells restrict macrophage maturation and stromal IL-6 limits the differentiation of cirrhosis-linked macrophages |
url | http://sfxeu10.hosted.exlibrisgroup.com/loughborough?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-24T11%3A55%3A43IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_swepu&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Liver%20stromal%20cells%20restrict%20macrophage%20maturation%20and%20stromal%20IL-6%20limits%20the%20differentiation%20of%20cirrhosis-linked%20macrophages&rft.jtitle=Journal%20of%20hepatology&rft.au=Buonomo,%20Erica%20L.&rft.date=2022-05-01&rft.volume=76&rft.issue=5&rft.spage=1127&rft.epage=1137&rft.pages=1127-1137&rft.issn=0168-8278&rft.eissn=1600-0641&rft_id=info:doi/10.1016/j.jhep.2021.12.036&rft_dat=%3Cproquest_swepu%3E2622657582%3C/proquest_swepu%3E%3Cgrp_id%3Ecdi_FETCH-LOGICAL-c472t-b774c98c52c78fb2c7f3b9274dd355182bf1aa61cdc9612ffd7028968b11f5d63%3C/grp_id%3E%3Coa%3E%3C/oa%3E%3Curl%3E%3C/url%3E&rft_id=info:oai/&rft_pqid=2695518890&rft_id=info:pmid/35074474&rfr_iscdi=true |