Integrated Single-Cell (Phospho-)Protein and RNA Detection Uncovers Phenotypic Characteristics and Active Signal Transduction of Human Antibody-Secreting Cells
Single-cell technologies are currently widely applied to obtain a deeper understanding of the phenotype of single-cells in heterogenous mixtures. However, integrated multilayer approaches including simultaneous detection of mRNA, protein expression, and intracellular phospho-proteins are still chall...
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Veröffentlicht in: | Molecular & cellular proteomics 2023-02, Vol.22 (2), p.100492, Article 100492 |
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creator | van Buijtenen, Erik Janssen, Wout Vink, Paul Habraken, Maurice J.M. Wingens, Laura J.A. van Elsas, Andrea Huck, Wilhelm T.S. van Buggenum, Jessie A.G.L. van Eenennaam, Hans |
description | Single-cell technologies are currently widely applied to obtain a deeper understanding of the phenotype of single-cells in heterogenous mixtures. However, integrated multilayer approaches including simultaneous detection of mRNA, protein expression, and intracellular phospho-proteins are still challenging. Here, we combined an adapted method to in vitro–differentiate peripheral B-cells into antibody-secreting cells (ASCs) (i.e., plasmablasts and plasma cells) with integrated multi-omic single-cell sequencing technologies to detect and quantify immunoglobulin subclass-specific surface markers, transcriptional profiles, and signaling transduction pathway components. Using a common set of surface proteins, we integrated two multimodal datasets to combine mRNA, protein expression, and phospho-protein detection in one integrated dataset. Next, we tested whether ASCs that only seem to differ in its ability to secrete different IgM, IgA, or IgG antibodies exhibit other differences that characterize these different ASCs. Our approach detected differential expression of plasmablast and plasma cell markers, homing receptors, and TNF receptors. In addition, differential sensitivity was observed for the different cytokine stimulations that were applied during in vitro differentiation. For example, IgM ASCs were more sensitive to IL-15, while IgG ASC responded more to IL-6 and IFN addition. Furthermore, tonic BCR activity was detected in IgA and IgM ASCs, while IgG ASC exhibited active BCR-independent SYK activity and NF-κB and mTOR signaling. We confirmed these findings using flow cytometry and small molecules inhibitors, demonstrating the importance of SYK, NF-κB, and mTOR activity for plasmablast/plasma cell differentiation/survival and/or IgG secretion. Taken together, our integrated multi-omics approach allowed high-resolution phenotypic characterization of single cells in a heterogenous sample of in vitro–differentiated human ASCs. Our strategy is expected to further our understanding of human ASCs in healthy and diseased samples and provide a valuable tool to identify novel biomarkers and potential drug targets.
[Display omitted]
•In-vitro differentiation of human B-cells into antibody-secreting cells.•Simultaneous single-cell detection of (phospho)-proteins and mRNA through sequencing.•MOFA+ allows data integration and phenotyping of IgM, IgG, and IgA cells.•Ig-class–specific transcriptome and expression of homing protein markers.•Signaling activity differs bet |
doi_str_mv | 10.1016/j.mcpro.2023.100492 |
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[Display omitted]
•In-vitro differentiation of human B-cells into antibody-secreting cells.•Simultaneous single-cell detection of (phospho)-proteins and mRNA through sequencing.•MOFA+ allows data integration and phenotyping of IgM, IgG, and IgA cells.•Ig-class–specific transcriptome and expression of homing protein markers.•Signaling activity differs between IgM, IgA, and IgG cells, including BCR and NF-κB.
Multi-modal single-cell sequencing technology enabled quantifying the characteristics of human antibody-secreting cells (ASCs). Integrative analysis identified three classes of ASCs and their molecular features, including surface protein markers, phospho-proteins, and transcriptional profiles. Each Ig-class of IgM, IgA, and IgG shows a specific expression of homing receptors and protein markers. IgM and IgA ASCs have tonic BCR signaling, while IgG has more active signaling pathways, including SYK, mTOR, IL6, and NF-kB.</description><identifier>ISSN: 1535-9476</identifier><identifier>ISSN: 1535-9484</identifier><identifier>EISSN: 1535-9484</identifier><identifier>DOI: 10.1016/j.mcpro.2023.100492</identifier><identifier>PMID: 36623694</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Antibody-Producing Cells - metabolism ; antibody-secreting cells ; Humans ; Immunoglobulin A ; Immunoglobulin G ; Immunoglobulin M ; multimodal ; NF-kappa B ; Phenotype ; plasmacells ; RNA ; RNA, Messenger - metabolism ; Signal Transduction ; Single-Cell Gene Expression Analysis ; single-cell phosphoproteomics ; TOR Serine-Threonine Kinases ; transcriptomics</subject><ispartof>Molecular & cellular proteomics, 2023-02, Vol.22 (2), p.100492, Article 100492</ispartof><rights>2023 The Authors</rights><rights>Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.</rights><rights>2023 The Authors 2023</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c459t-ab9642f6106e36c2ad709bd3376d85e02fa1b6f08644d8c32a1aa44a075bc9493</citedby><cites>FETCH-LOGICAL-c459t-ab9642f6106e36c2ad709bd3376d85e02fa1b6f08644d8c32a1aa44a075bc9493</cites><orcidid>0000-0003-0099-3738 ; 0000-0001-8348-5979 ; 0000-0002-9823-1450</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC9943876/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC9943876/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,27924,27925,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/36623694$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>van Buijtenen, Erik</creatorcontrib><creatorcontrib>Janssen, Wout</creatorcontrib><creatorcontrib>Vink, Paul</creatorcontrib><creatorcontrib>Habraken, Maurice J.M.</creatorcontrib><creatorcontrib>Wingens, Laura J.A.</creatorcontrib><creatorcontrib>van Elsas, Andrea</creatorcontrib><creatorcontrib>Huck, Wilhelm T.S.</creatorcontrib><creatorcontrib>van Buggenum, Jessie A.G.L.</creatorcontrib><creatorcontrib>van Eenennaam, Hans</creatorcontrib><title>Integrated Single-Cell (Phospho-)Protein and RNA Detection Uncovers Phenotypic Characteristics and Active Signal Transduction of Human Antibody-Secreting Cells</title><title>Molecular & cellular proteomics</title><addtitle>Mol Cell Proteomics</addtitle><description>Single-cell technologies are currently widely applied to obtain a deeper understanding of the phenotype of single-cells in heterogenous mixtures. However, integrated multilayer approaches including simultaneous detection of mRNA, protein expression, and intracellular phospho-proteins are still challenging. Here, we combined an adapted method to in vitro–differentiate peripheral B-cells into antibody-secreting cells (ASCs) (i.e., plasmablasts and plasma cells) with integrated multi-omic single-cell sequencing technologies to detect and quantify immunoglobulin subclass-specific surface markers, transcriptional profiles, and signaling transduction pathway components. Using a common set of surface proteins, we integrated two multimodal datasets to combine mRNA, protein expression, and phospho-protein detection in one integrated dataset. Next, we tested whether ASCs that only seem to differ in its ability to secrete different IgM, IgA, or IgG antibodies exhibit other differences that characterize these different ASCs. Our approach detected differential expression of plasmablast and plasma cell markers, homing receptors, and TNF receptors. In addition, differential sensitivity was observed for the different cytokine stimulations that were applied during in vitro differentiation. For example, IgM ASCs were more sensitive to IL-15, while IgG ASC responded more to IL-6 and IFN addition. Furthermore, tonic BCR activity was detected in IgA and IgM ASCs, while IgG ASC exhibited active BCR-independent SYK activity and NF-κB and mTOR signaling. We confirmed these findings using flow cytometry and small molecules inhibitors, demonstrating the importance of SYK, NF-κB, and mTOR activity for plasmablast/plasma cell differentiation/survival and/or IgG secretion. Taken together, our integrated multi-omics approach allowed high-resolution phenotypic characterization of single cells in a heterogenous sample of in vitro–differentiated human ASCs. Our strategy is expected to further our understanding of human ASCs in healthy and diseased samples and provide a valuable tool to identify novel biomarkers and potential drug targets.
[Display omitted]
•In-vitro differentiation of human B-cells into antibody-secreting cells.•Simultaneous single-cell detection of (phospho)-proteins and mRNA through sequencing.•MOFA+ allows data integration and phenotyping of IgM, IgG, and IgA cells.•Ig-class–specific transcriptome and expression of homing protein markers.•Signaling activity differs between IgM, IgA, and IgG cells, including BCR and NF-κB.
Multi-modal single-cell sequencing technology enabled quantifying the characteristics of human antibody-secreting cells (ASCs). Integrative analysis identified three classes of ASCs and their molecular features, including surface protein markers, phospho-proteins, and transcriptional profiles. Each Ig-class of IgM, IgA, and IgG shows a specific expression of homing receptors and protein markers. IgM and IgA ASCs have tonic BCR signaling, while IgG has more active signaling pathways, including SYK, mTOR, IL6, and NF-kB.</description><subject>Antibody-Producing Cells - metabolism</subject><subject>antibody-secreting cells</subject><subject>Humans</subject><subject>Immunoglobulin A</subject><subject>Immunoglobulin G</subject><subject>Immunoglobulin M</subject><subject>multimodal</subject><subject>NF-kappa B</subject><subject>Phenotype</subject><subject>plasmacells</subject><subject>RNA</subject><subject>RNA, Messenger - metabolism</subject><subject>Signal Transduction</subject><subject>Single-Cell Gene Expression Analysis</subject><subject>single-cell phosphoproteomics</subject><subject>TOR Serine-Threonine Kinases</subject><subject>transcriptomics</subject><issn>1535-9476</issn><issn>1535-9484</issn><issn>1535-9484</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2023</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kd9u0zAYxSMEYmPwBEjIl-MixbEdJ7kAqSp_NmmCim3XlmN_aVwldmc7lfo0vCruMiq44cqW_TvnO_bJsrcFXhS44B-2i1HtvFsQTGg6wawhz7LzoqRl3rCaPT_tK36WvQphizHBRVW-zM4o54Tyhp1nv65thI2XETS6NXYzQL6CYUCX696FXe_y92vvIhiLpNXo5_cl-gwRVDTOonur3B58QOserIuHnVFo1UsvVQRvQjQqPKqWCd9Dst9YOaA7L23Q02zhOnQ1jdKipY2mdfqQ34LyEFMSdMwRXmcvOjkEePO0XmT3X7_cra7ymx_frlfLm1yxsom5bBvOSMcLzIFyRaSucNNqSiuu6xIw6WTR8g7XnDFdK0pkISVjEldlqxrW0Ivs0-y7m9oRtAIbvRzEzptR-oNw0oh_b6zpxcbtRdMwWlc8GVw-GXj3MEGIYjRBpSdIC24KgiSGUkYoSyidUeVdCB6605gCi2O1YiseqxXHasVcbVK9-zvhSfOnywR8nAFI_7Q34EVQBqwCbXxqTGhn_jvgN2jouaY</recordid><startdate>20230201</startdate><enddate>20230201</enddate><creator>van Buijtenen, Erik</creator><creator>Janssen, Wout</creator><creator>Vink, Paul</creator><creator>Habraken, Maurice J.M.</creator><creator>Wingens, Laura J.A.</creator><creator>van Elsas, Andrea</creator><creator>Huck, Wilhelm T.S.</creator><creator>van Buggenum, Jessie A.G.L.</creator><creator>van Eenennaam, Hans</creator><general>Elsevier Inc</general><general>American Society for Biochemistry and Molecular Biology</general><scope>6I.</scope><scope>AAFTH</scope><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>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0003-0099-3738</orcidid><orcidid>https://orcid.org/0000-0001-8348-5979</orcidid><orcidid>https://orcid.org/0000-0002-9823-1450</orcidid></search><sort><creationdate>20230201</creationdate><title>Integrated Single-Cell (Phospho-)Protein and RNA Detection Uncovers Phenotypic Characteristics and Active Signal Transduction of Human Antibody-Secreting Cells</title><author>van Buijtenen, Erik ; Janssen, Wout ; Vink, Paul ; Habraken, Maurice J.M. ; Wingens, Laura J.A. ; van Elsas, Andrea ; Huck, Wilhelm T.S. ; van Buggenum, Jessie A.G.L. ; van Eenennaam, Hans</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c459t-ab9642f6106e36c2ad709bd3376d85e02fa1b6f08644d8c32a1aa44a075bc9493</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2023</creationdate><topic>Antibody-Producing Cells - metabolism</topic><topic>antibody-secreting cells</topic><topic>Humans</topic><topic>Immunoglobulin A</topic><topic>Immunoglobulin G</topic><topic>Immunoglobulin M</topic><topic>multimodal</topic><topic>NF-kappa B</topic><topic>Phenotype</topic><topic>plasmacells</topic><topic>RNA</topic><topic>RNA, Messenger - metabolism</topic><topic>Signal Transduction</topic><topic>Single-Cell Gene Expression Analysis</topic><topic>single-cell phosphoproteomics</topic><topic>TOR Serine-Threonine Kinases</topic><topic>transcriptomics</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>van Buijtenen, Erik</creatorcontrib><creatorcontrib>Janssen, Wout</creatorcontrib><creatorcontrib>Vink, Paul</creatorcontrib><creatorcontrib>Habraken, Maurice J.M.</creatorcontrib><creatorcontrib>Wingens, Laura J.A.</creatorcontrib><creatorcontrib>van Elsas, Andrea</creatorcontrib><creatorcontrib>Huck, Wilhelm T.S.</creatorcontrib><creatorcontrib>van Buggenum, Jessie A.G.L.</creatorcontrib><creatorcontrib>van Eenennaam, Hans</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Molecular & cellular proteomics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>van Buijtenen, Erik</au><au>Janssen, Wout</au><au>Vink, Paul</au><au>Habraken, Maurice J.M.</au><au>Wingens, Laura J.A.</au><au>van Elsas, Andrea</au><au>Huck, Wilhelm T.S.</au><au>van Buggenum, Jessie A.G.L.</au><au>van Eenennaam, Hans</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Integrated Single-Cell (Phospho-)Protein and RNA Detection Uncovers Phenotypic Characteristics and Active Signal Transduction of Human Antibody-Secreting Cells</atitle><jtitle>Molecular & cellular proteomics</jtitle><addtitle>Mol Cell Proteomics</addtitle><date>2023-02-01</date><risdate>2023</risdate><volume>22</volume><issue>2</issue><spage>100492</spage><pages>100492-</pages><artnum>100492</artnum><issn>1535-9476</issn><issn>1535-9484</issn><eissn>1535-9484</eissn><abstract>Single-cell technologies are currently widely applied to obtain a deeper understanding of the phenotype of single-cells in heterogenous mixtures. However, integrated multilayer approaches including simultaneous detection of mRNA, protein expression, and intracellular phospho-proteins are still challenging. Here, we combined an adapted method to in vitro–differentiate peripheral B-cells into antibody-secreting cells (ASCs) (i.e., plasmablasts and plasma cells) with integrated multi-omic single-cell sequencing technologies to detect and quantify immunoglobulin subclass-specific surface markers, transcriptional profiles, and signaling transduction pathway components. Using a common set of surface proteins, we integrated two multimodal datasets to combine mRNA, protein expression, and phospho-protein detection in one integrated dataset. Next, we tested whether ASCs that only seem to differ in its ability to secrete different IgM, IgA, or IgG antibodies exhibit other differences that characterize these different ASCs. Our approach detected differential expression of plasmablast and plasma cell markers, homing receptors, and TNF receptors. In addition, differential sensitivity was observed for the different cytokine stimulations that were applied during in vitro differentiation. For example, IgM ASCs were more sensitive to IL-15, while IgG ASC responded more to IL-6 and IFN addition. Furthermore, tonic BCR activity was detected in IgA and IgM ASCs, while IgG ASC exhibited active BCR-independent SYK activity and NF-κB and mTOR signaling. We confirmed these findings using flow cytometry and small molecules inhibitors, demonstrating the importance of SYK, NF-κB, and mTOR activity for plasmablast/plasma cell differentiation/survival and/or IgG secretion. Taken together, our integrated multi-omics approach allowed high-resolution phenotypic characterization of single cells in a heterogenous sample of in vitro–differentiated human ASCs. Our strategy is expected to further our understanding of human ASCs in healthy and diseased samples and provide a valuable tool to identify novel biomarkers and potential drug targets.
[Display omitted]
•In-vitro differentiation of human B-cells into antibody-secreting cells.•Simultaneous single-cell detection of (phospho)-proteins and mRNA through sequencing.•MOFA+ allows data integration and phenotyping of IgM, IgG, and IgA cells.•Ig-class–specific transcriptome and expression of homing protein markers.•Signaling activity differs between IgM, IgA, and IgG cells, including BCR and NF-κB.
Multi-modal single-cell sequencing technology enabled quantifying the characteristics of human antibody-secreting cells (ASCs). Integrative analysis identified three classes of ASCs and their molecular features, including surface protein markers, phospho-proteins, and transcriptional profiles. Each Ig-class of IgM, IgA, and IgG shows a specific expression of homing receptors and protein markers. IgM and IgA ASCs have tonic BCR signaling, while IgG has more active signaling pathways, including SYK, mTOR, IL6, and NF-kB.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>36623694</pmid><doi>10.1016/j.mcpro.2023.100492</doi><orcidid>https://orcid.org/0000-0003-0099-3738</orcidid><orcidid>https://orcid.org/0000-0001-8348-5979</orcidid><orcidid>https://orcid.org/0000-0002-9823-1450</orcidid><oa>free_for_read</oa></addata></record> |
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subjects | Antibody-Producing Cells - metabolism antibody-secreting cells Humans Immunoglobulin A Immunoglobulin G Immunoglobulin M multimodal NF-kappa B Phenotype plasmacells RNA RNA, Messenger - metabolism Signal Transduction Single-Cell Gene Expression Analysis single-cell phosphoproteomics TOR Serine-Threonine Kinases transcriptomics |
title | Integrated Single-Cell (Phospho-)Protein and RNA Detection Uncovers Phenotypic Characteristics and Active Signal Transduction of Human Antibody-Secreting Cells |
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