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A specific inflammatory suppression fibroblast subpopulation characterized by MHCII expression in human dilated cardiomyopathy

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Abstract

Dilated cardiomyopathy (DCM) is a significant cause of heart failure that requires heart transplantation. Fibroblasts play a central role in the fibro-inflammatory microenvironment of DCM. However, their cellular heterogeneity and interaction with immune cells have not been well identified. An integrative analysis was conducted on single-cell RNA sequencing (ScRNA-Seq) data from human left ventricle tissues, which comprised 4 hearts from healthy donors and 6 hearts with DCM. The specific antigen-presenting fibroblast (apFB) was explored as a subtype of fibroblasts characterized by expressing MHCII genes, the existence of which was confirmed by immunofluorescence staining of 3 cardiac tissues from DCM patients with severe heart failure. apFB highly expressed the genes that response to IFN-γ, and it also have a high activity of the JAK-STAT pathway and the transcription factor RFX5. In addition, the analysis of intercellular communication between apFBs and CD4+T cells revealed that the anti-inflammatory ligand-receptor pairs TGFB-TGFR, CLEC2B-KLRB1, and CD46-JAG1 were upregulated in DCM. The apFB signature exhibited a positive correlation with immunosuppression and demonstrated diagnostic and prognostic value when evaluated using a bulk RNA dataset comprising 166 donors and 166 DCM samples. In conclusion, the present study identified a novel subpopulation of fibroblasts that specifically expresses MHCII-encoding genes. This specific apFBs can suppress the inflammation occurring in DCM. Our findings further elucidate the composition of the fibro-inflammatory microenvironment in DCM, and provide a novel therapeutic target.

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Data availability

The sequencing data used in this study (GSE145154, GSE183852, and GSE141910) are available from the GEO database (https://www.ncbi.nlm.nih.gov/geo/). The code used in this study is available upon request by contacting the corresponding author.

References

  1. Kiadaliri AA (2018) Global, regional, and national incidence, prevalence, and years lived with disability for 354 diseases and injuries for 195 countries and territories, 1990–2017: a systematic analysis for the global burden of disease study 2017. The Lancet 392:1789–1858

    Article  Google Scholar 

  2. Weintraub RG, Semsarian C, Macdonald P (2017) Dilated cardiomyopathy. The Lancet 390:400–414

    Article  CAS  Google Scholar 

  3. Zeng C, Duan F, Hu J, Luo B, Huang B, Lou X, Sun X, Li H, Zhang X, Yin S (2020) NLRP3 inflammasome-mediated pyroptosis contributes to the pathogenesis of non-ischemic dilated cardiomyopathy. Redox Biol 34:101523

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  4. Mizoguchi F, Slowikowski K, Wei K, Marshall JL, Rao DA, Chang SK, Nguyen HN, Noss EH, Turner JD, Earp BE (2018) Functionally distinct disease-associated fibroblast subsets in rheumatoid arthritis. Nat Commun 9:1–11

    Article  ADS  CAS  Google Scholar 

  5. Humeres C, Vivar R, Boza P, Munoz C, Bolivar S, Anfossi R, Osorio JM, Olivares-Silva F, Garcia L, Diaz-Araya G (2016) Cardiac fibroblast cytokine profiles induced by proinflammatory or profibrotic stimuli promote monocyte recruitment and modulate macrophage M1/M2 balance in vitro. J Mol Cell Cardiol 101:69–80

    Article  CAS  Google Scholar 

  6. Bansal SS, Ismahil MA, Goel M, Zhou G, Rokosh G, Hamid T, Prabhu SD (2019) Dysfunctional and proinflammatory regulatory T-lymphocytes are essential for adverse cardiac remodeling in ischemic cardiomyopathy. Circulation 139:206–221

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  7. Bajpai G, Schneider C, Wong N, Bredemeyer A, Hulsmans M, Nahrendorf M, Epelman S, Kreisel D, Liu Y, Itoh A, Shankar TS, Selzman CH, Drakos SG, Lavine KJ (2018) The human heart contains distinct macrophage subsets with divergent origins and functions. Nat Med 24:1234–1245

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  8. Rao M, Wang X, Guo G, Wang L, Chen S, Yin P, Chen K, Chen L, Zhang Z, Chen X, Hu X, Hu S, Song J (2021) Resolving the intertwining of inflammation and fibrosis in human heart failure at single-cell level. Basic Res Cardiol 116:55

    Article  PubMed  Google Scholar 

  9. Wang L, Yu P, Zhou B, Song J, Li Z, Zhang M, Guo G, Wang Y, Chen X, Han L, Hu S (2020) Single-cell reconstruction of the adult human heart during heart failure and recovery reveals the cellular landscape underlying cardiac function. Nat Cell Biol 22:108–119

    Article  PubMed  Google Scholar 

  10. Tallquist MD (2020) Cardiac fibroblast diversity. Annu Rev Physiol 82:63–78

    Article  PubMed  CAS  Google Scholar 

  11. Nicin L, Abplanalp WT, Schanzer A, Sprengel A, John D, Mellentin H, Tombor L, Keuper M, Ullrich E, Klingel K, Dettmeyer RB, Hoffmann J, Akintuerk H, Jux C, Schranz D, Zeiher AM, Rupp S, Dimmeler S (2021) Single nuclei sequencing reveals novel insights into the regulation of cellular signatures in children with dilated cardiomyopathy. Circulation 143:1704–1719

    Article  PubMed  CAS  Google Scholar 

  12. Elyada E, Bolisetty M, Laise P, Flynn WF, Courtois ET, Burkhart RA, Teinor JA, Belleau P, Biffi G, Lucito MS (2019) Cross-species single-cell analysis of pancreatic ductal adenocarcinoma reveals antigen-presenting cancer-associated fibroblasts. Cancer Discov 9:1102–1123

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. Huang H, Wang Z, Zhang Y, Pradhan RN, Ganguly D, Chandra R, Murimwa G, Wright S, Gu X, Maddipati R, Muller S, Turley SJ, Brekken RA (2022) Mesothelial cell-derived antigen-presenting cancer-associated fibroblasts induce expansion of regulatory T cells in pancreatic cancer. Cancer Cell 9:3922

    Google Scholar 

  14. Koenig AL, Shchukina I, Amrute J, Andhey PS, Zaitsev K, Lai L, Bajpai G, Bredemeyer A, Smith G, Jones C, Terrebonne E, Rentschler SL, Artyomov MN, Lavine KJ (2022) Single-cell transcriptomics reveals cell-type-specific diversification in human heart failure. Nature Cardiovascular Research 1:263–280

    Article  PubMed  PubMed Central  Google Scholar 

  15. Korsunsky I, Millard N, Fan J, Slowikowski K, Zhang F, Wei K, Baglaenko Y, Brenner M, LohRaychaudhuri P-rS (2019) Fast, sensitive and accurate integration of single-cell data with Harmony. Nat methods 16:1289–1296

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. Zappia L, Oshlack A (2018) Clustering trees: a visualization for evaluating clusterings at multiple resolutions. Gigascience. https://doi.org/10.1093/gigascience/giy083

    Article  PubMed  PubMed Central  Google Scholar 

  17. Finak G, McDavid A, Yajima M, Deng J, Gersuk V, Shalek AK, Slichter CK, Miller HW, McElrath MJ, Prlic M (2015) MAST: a flexible statistical framework for assessing transcriptional changes and characterizing heterogeneity in single-cell RNA sequencing data. Genome Biol 16:1–13

    Article  Google Scholar 

  18. Kolberg L, Raudvere U, Kuzmin I, Vilo J, Peterson H (2020) gprofiler2–an R package for gene list functional enrichment analysis and namespace conversion toolset g: profiler. F1000Res 9:709. https://doi.org/10.12688/f1000research.24956.1

    Article  Google Scholar 

  19. Ashburner M, Ball CA, Blake JA, Botstein D, Butler H, Cherry JM, Davis AP, Dolinski K, Dwight SS, Eppig JT (2000) Gene ontology: tool for the unification of biology. Nat Genet 25:25–29

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. Jassal B, Matthews L, Viteri G, Gong C, Lorente P, Fabregat A, Sidiropoulos K, Cook J, Gillespie M, Haw R (2020) The reactome pathway knowledgebase. Nucleic Acids Res 48:D498–D503

    PubMed  CAS  Google Scholar 

  21. Kanehisa M, Sato Y, Furumichi M, Morishima K, Tanabe M (2019) New approach for understanding genome variations in KEGG. Nucleic Acids Res 47:D590–D595

    Article  PubMed  CAS  Google Scholar 

  22. Shao X, Taha IN, Clauser KR, Gao Y, Naba A (2020) MatrisomeDB: the ECM-protein knowledge database. Nucleic Acids Res 48:D1136–D1144

    Article  PubMed  CAS  Google Scholar 

  23. Alvarez MJ, Shen Y, Giorgi FM, Lachmann A, Ding BB, Ye BH, Califano A (2016) Functional characterization of somatic mutations in cancer using network-based inference of protein activity. Nat Genet 48:838–847

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. Holland CH, Tanevski J, Perales-Patón J, Gleixner J, Kumar MP, Mereu E, Joughin BA, Stegle O, Lauffenburger DA, Heyn H (2020) Robustness and applicability of transcription factor and pathway analysis tools on single-cell RNA-seq data. Genome Biol 21:1–19

    Article  Google Scholar 

  25. Jin S, Guerrero-Juarez CF, Zhang L, Chang I, Ramos R, Kuan C-H, Myung P, Plikus MV, Nie Q (2021) Inference and analysis of cell-cell communication using cell chat. Nat Commun 12:1–20

    Article  Google Scholar 

  26. Dobin A, Davis CA, Schlesinger F, Drenkow J, Zaleski C, Jha S, Batut P, Chaisson M, Gingeras TR (2013) STAR: ultrafast universal RNA-seq aligner. Bioinformatics 29:15–21

    Article  PubMed  CAS  Google Scholar 

  27. Reimand J, Kull M, Peterson H, Hansen J, Vilo J (2007) g: Profiler—a web-based toolset for functional profiling of gene lists from large-scale experiments. Nucleic Acids Res 35:W193–W200

    Article  PubMed  PubMed Central  Google Scholar 

  28. Reith W, LeibundGut-Landmann S, Waldburger J-M (2005) Regulation of MHC class II gene expression by the class II transactivator. Nat Rev Immunol 5:793–806

    Article  PubMed  CAS  Google Scholar 

  29. Zheng L, Qin S, Si W, Wang A, Xing B, Gao R, Ren X, Wang L, Wu X, Zhang J, Wu N, Zhang N, Zheng H, Ouyang H, Chen K, Bu Z, Hu X, Ji J, Zhang Z (2021) Pan-cancer single-cell landscape of tumor-infiltrating T cells. Science 374:abe6474

    Article  PubMed  Google Scholar 

  30. Sun K, Xu R, Ma F, Yang N, Li Y, Sun X, Jin P, Kang W, Jia L, Xiong J (2022) scRNA-seq of gastric tumor shows complex intercellular interaction with an alternative T cell exhaustion trajectory. Nat Commun 13:1–19

    Google Scholar 

  31. Wherry EJ, Kurachi M (2015) Molecular and cellular insights into T cell exhaustion. Nat Rev Immunol 15:486–499

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  32. Chen W, Ten Dijke P (2016) Immunoregulation by members of the TGFβ superfamily. Nat Rev Immunol 16:723–740

    Article  PubMed  Google Scholar 

  33. Veldhoen M, Hocking RJ, Atkins CJ, Locksley RM, Stockinger B (2006) TGFβ in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells. Immunity 24:179–189

    Article  PubMed  CAS  Google Scholar 

  34. Weber KT, Díez J (2016) Targeting the cardiac myofibroblast secretome to treat myocardial fibrosis in heart failure. Circ: Heart Fail 9:e003315

    PubMed  Google Scholar 

  35. Nagaraju CK, Robinson EL, Abdesselem M, Trenson S, Dries E, Gilbert G, Janssens S, Van Cleemput J, Rega F, Meyns B (2019) Myofibroblast phenotype and reversibility of fibrosis in patients with end-stage heart failure. J Am Coll Cardiol 73:2267–2282

    Article  PubMed  Google Scholar 

  36. Harding D, Chong MHA, Lahoti N, Bigogno CM, Prema R, Mohiddin SA et al (2023) Dilated cardiomyopathy and chronic cardiac inflammation: pathogenesis, diagnosis and therapy. J Intern Med 293(1):23–47

    Article  PubMed  CAS  Google Scholar 

  37. Immunomodulatory Cell Therapy Using αGalCer-Pulsed Dendritic Cells Ameliorates Heart Failure in a Murine Dilated Cardiomyopathy Model - PubMed [Internet]. [cited 2024 Jan 7]. Available from: https://pubmed.ncbi.nlm.nih.gov/36268712/

  38. Gogiraju R, Bochenek ML, Schäfer K (2019) Angiogenic endothelial cell signaling in cardiac hypertrophy and heart failure. Front Cardiovasc Med 6:20

    Article  ADS  PubMed  PubMed Central  CAS  Google Scholar 

  39. Shiojima I, Sato K, Izumiya Y, Schiekofer S, Ito M, Liao R et al (2005) Disruption of coordinated cardiac hypertrophy and angiogenesis contributes to the transition to heart failure. J Clin Invest 115(8):2108–2118

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  40. Gogiraju R, Xu X, Bochenek ML, Steinbrecher JH, Lehnart SE, Wenzel P et al (2015) Endothelial p53 deletion improves angiogenesis and prevents cardiac fibrosis and heart failure induced by pressure overload in mice. J Am Heart Assoc 4(2):e001770

    Article  PubMed  PubMed Central  Google Scholar 

  41. Tucker W, Tucker B, Rye K-A, Ong KL (2022) Fibroblast growth factor 21 in heart failure. Heart Fail Rev 28:1–12

    Article  Google Scholar 

  42. Bradshaw AD, DeLeon-Pennell KY (2020) T-cell regulation of fibroblasts and cardiac fibrosis. Matrix Biol 91:167–175

    Article  PubMed  Google Scholar 

  43. McLellan MA, Skelly DA, Dona MSI, Squiers GT, Farrugia GE, Gaynor TL et al (2020) High-resolution transcriptomic profiling of the heart during chronic stress reveals cellular drivers of cardiac fibrosis and hypertrophy. Circulation 142(15):1448–1463

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  44. Forte E, Skelly DA, Chen M, Daigle S, Morelli KA, Hon O et al (2020) Dynamic interstitial cell response during myocardial infarction predicts resilience to rupture in genetically diverse mice. Cell Rep 30(9):3149-3163.e6

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  45. Boots A, Wimmers-Bertens A, Rijnders A (1994) Antigen-presenting capacity of rheumatoid synovial fibroblasts. Immunology 82:268

    PubMed  PubMed Central  CAS  Google Scholar 

  46. Friedman G, Levi-Galibov O, David E, Bornstein C, Giladi A, Dadiani M, Mayo A, Halperin C, Pevsner-Fischer M, Lavon H (2020) Cancer-associated fibroblast compositions change with breast cancer progression linking the ratio of S100A4+ and PDPN+ CAFs to clinical outcome. Nature Cancer 1:692–708

    Article  PubMed  CAS  Google Scholar 

  47. Kerdidani D, Goudevenou K, Aerakis E (2020) Antigen-presenting fibroblasts sustain anti-tumour CD4+ T cells in situ via MHCIIp-TCR and C1q–C1qbp binding. BioRxiv 130(4):1492–1494. https://doi.org/10.4049/jimmunol.130.4.1492

    Article  Google Scholar 

  48. Basham T, Merigan TC (1983) Recombinant interferon-gamma increases HLA-DR synthesis and expression. J Immunol 130:1492–1494

    Article  PubMed  CAS  Google Scholar 

  49. Alvaro-Gracia JM, Zvaifler NJ, Firestein GS (1990) Cytokines in chronic inflammatory arthritis. V. Mutual antagonism between interferon-gamma and tumor necrosis factor-alpha on HLA-DR expression, proliferation, collagenase production, and granulocyte macrophage colony-stimulating factor production by rheumatoid arthritis synoviocytes. J clinical investigation 86:1790–1798

    Article  CAS  Google Scholar 

  50. Phillips R (2021) NK cells induce a pro-inflammatory phenotype in RA synovial fibroblasts. Nat Rev Rheumatol 17:645–645

    PubMed  Google Scholar 

  51. Myers DR, Zikherman J, Roose JP (2017) Tonic signals: why do lymphocytes bother? Trends Immunol 38:844–857

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  52. Mathewson ND, Ashenberg O, Tirosh I, Gritsch S, Perez EM, Marx S, Jerby-Arnon L, Chanoch-Myers R, Hara T, Richman AR (2021) Inhibitory CD161 receptor identified in glioma-infiltrating T cells by single-cell analysis. Cell 184(1281–1298):e26

    Google Scholar 

  53. Le Friec G, Sheppard D, Whiteman P, Karsten CM, Shamoun SA-T, Laing A, Bugeon L, Dallman MJ, Melchionna T, Chillakuri C (2012) The CD46-jagged1 interaction is critical for human TH1 immunity. Nat immunol 13:1213–1221

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors thank Dr Peiran, Huang for helpful comments and suggestions regarding data analysis and display.

Funding

This work was supported by the National Natural Science Foundation of China (82370377, 81601663), Natural Science Foundation of Shanghai (23ZR1408800), and the Natural Science Foundation of Hebei Province of China (C20200206025).

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Authors and Affiliations

  1. Department of Cardiothoracic Surgery, Huashan Hospital of Fudan University, 12 Wulumuqi Rd, Shanghai, 200040, China

    Xi Fan, Kai Huang, Liewen Pang, Yiqing Wang & Xiaotian Sun

  2. Department of Physiology, Hebei Medical University, Shijiazhuang, China

    Yuming Wu & Sheng Jin

  3. Department of Cardiology, Huashan Hospital of Fudan University, 12 Wulumuqi Rd, Shanghai, 200040, China

    Bo Jin

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  1. Xi Fan
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Contributions

XS and XF conceived and designed this study. XF, BJ, and K.H. contributed to data analysis, histological experiments, and the original draft. YW, XS, YW, SJ and LP. participated in writing- review and editing. All authors reviewed the final manuscript.

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Correspondence to Yiqing Wang, Bo Jin or Xiaotian Sun.

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Fan, X., Huang, K., Wu, Y. et al. A specific inflammatory suppression fibroblast subpopulation characterized by MHCII expression in human dilated cardiomyopathy. Mol Cell Biochem (2024). https://doi.org/10.1007/s11010-024-04939-9

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