IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v16y2025i1d10.1038_s41467-025-61214-1.html
   My bibliography  Save this article

Spatial and single cell mapping of castleman disease reveals key stromal cell types and cytokine pathways

Author

Listed:
  • David Smith

    (Children’s Hospital of Philadelphia Research Institute)

  • Anna Eichinger

    (New York University Grossman School of Medicine
    Ludwig-Maximilians-Universität München)

  • Éanna Fennell

    (University of Limerick)

  • Zijun Y. Xu-Monette

    (Duke University Medical Center)

  • Andrew Rech

    (The Children’s Hospital of Philadelphia and the University of Pennsylvania)

  • Julia Wang

    (The Children’s Hospital of Philadelphia and the University of Pennsylvania)

  • Eduardo Esteva

    (New York University Grossman School of Medicine)

  • Arta Seyedian

    (The Children’s Hospital of Philadelphia)

  • Xiaoxu Yang

    (Children’s Hospital of Philadelphia Research Institute)

  • Mei Zhang

    (Children’s Hospital of Philadelphia Research Institute)

  • Dan Martinez

    (University of Limerick)

  • Kai Tan

    (Children’s Hospital of Philadelphia Research Institute
    The Children’s Hospital of Philadelphia)

  • Minjie Luo

    (University of Limerick)

  • Katherine J. Young

    (Duke University Medical Center)

  • Paul G. Murray

    (University of Limerick)

  • Christopher Park

    (New York University Grossman School of Medicine)

  • Boris Reizis

    (New York University Grossman School of Medicine)

  • Vinodh Pillai

    (The Children’s Hospital of Philadelphia and the University of Pennsylvania)

Abstract

To determine the cellular and molecular basis of Castleman Disease (CD), we analyze the spatial proteome and transcriptome from a discovery (n = 9 cases) and validation (n = 13 cases) cohort of Unicentric CD, idiopathic Multicentric CD, HHV8-associated MCD, and reactive lymph nodes. CD shows increased stromal cells that form unique microenvironments. Interaction of activated follicular dendritic cell (FDC) cytoplasmic meshworks with mantle-zone B cells is associated with B-cell activation and differentiation. CXCL13+ FDCs, PDGFRA + T-zone reticular cells (TRC), and ACTA2-positive perivascular reticular cells (PRC) were the predominant source of increased VEGF expression and IL-6 signaling. MCD is characterized by increased TRC while UCD shows increased B-reticular cells (BRC). VEGF expression by FDCs is associated with peri-follicular neovascularization. FDC, TRC and PRC of CD activates JAK-STAT, TGFβ, and MAPK pathways via specific ligand-receptor interactions. Here, we show that stromal-cell activation and associated B cell activation and differentiation, neovascularization and stromal remodeling underlie CD.

Suggested Citation

  • David Smith & Anna Eichinger & Éanna Fennell & Zijun Y. Xu-Monette & Andrew Rech & Julia Wang & Eduardo Esteva & Arta Seyedian & Xiaoxu Yang & Mei Zhang & Dan Martinez & Kai Tan & Minjie Luo & Katheri, 2025. "Spatial and single cell mapping of castleman disease reveals key stromal cell types and cytokine pathways," Nature Communications, Nature, vol. 16(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-61214-1
    DOI: 10.1038/s41467-025-61214-1
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-025-61214-1
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-025-61214-1?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Erick Armingol & Hratch M. Baghdassarian & Cameron Martino & Araceli Perez-Lopez & Caitlin Aamodt & Rob Knight & Nathan E. Lewis, 2022. "Context-aware deconvolution of cell–cell communication with Tensor-cell2cell," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    2. Michael Schubert & Bertram Klinger & Martina Klünemann & Anja Sieber & Florian Uhlitz & Sascha Sauer & Mathew J. Garnett & Nils Blüthgen & Julio Saez-Rodriguez, 2018. "Perturbation-response genes reveal signaling footprints in cancer gene expression," Nature Communications, Nature, vol. 9(1), pages 1-11, December.
    3. Daniel Dimitrov & Dénes Türei & Martin Garrido-Rodriguez & Paul L. Burmedi & James S. Nagai & Charlotte Boys & Ricardo O. Ramirez Flores & Hyojin Kim & Bence Szalai & Ivan G. Costa & Alberto Valdeoliv, 2022. "Comparison of methods and resources for cell-cell communication inference from single-cell RNA-Seq data," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Erick Armingol & Hratch M. Baghdassarian & Cameron Martino & Araceli Perez-Lopez & Caitlin Aamodt & Rob Knight & Nathan E. Lewis, 2022. "Context-aware deconvolution of cell–cell communication with Tensor-cell2cell," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    2. Guillermo Serrano & Nerea Berastegui & Aintzane Díaz-Mazkiaran & Paula García-Olloqui & Carmen Rodriguez-Res & Sofia Huerga-Dominguez & Marina Ainciburu & Amaia Vilas-Zornoza & Patxi San Martin-Uriz &, 2024. "Single-cell transcriptional profile of CD34+ hematopoietic progenitor cells from del(5q) myelodysplastic syndromes and impact of lenalidomide," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    3. Adrian B. Levine & Liana Nobre & Anirban Das & Scott Milos & Vanessa Bianchi & Monique Johnson & Nicholas R. Fernandez & Lucie Stengs & Scott Ryall & Michelle Ku & Mansuba Rana & Benjamin Laxer & Java, 2024. "Immuno-oncologic profiling of pediatric brain tumors reveals major clinical significance of the tumor immune microenvironment," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    4. Sina Schumacher & Max Fernkorn & Michelle Marten & Rui Chen & Yung Su Kim & Ivan Bedzhov & Christian Schröter, 2024. "Tissue-intrinsic beta-catenin signals antagonize Nodal-driven anterior visceral endoderm differentiation," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    5. Fabian Peisker & Maurice Halder & James Nagai & Susanne Ziegler & Nadine Kaesler & Konrad Hoeft & Ronghui Li & Eric M. J. Bindels & Christoph Kuppe & Julia Moellmann & Michael Lehrke & Christian Stopp, 2022. "Mapping the cardiac vascular niche in heart failure," Nature Communications, Nature, vol. 13(1), pages 1-20, December.
    6. Sara M. Parigi & Ludvig Larsson & Srustidhar Das & Ricardo O. Ramirez Flores & Annika Frede & Kumar P. Tripathi & Oscar E. Diaz & Katja Selin & Rodrigo A. Morales & Xinxin Luo & Gustavo Monasterio & C, 2022. "The spatial transcriptomic landscape of the healing mouse intestine following damage," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    7. L. Mathur & B. Szalai & N. H. Du & R. Utharala & M. Ballinger & J. J. M. Landry & M. Ryckelynck & V. Benes & J. Saez-Rodriguez & C. A. Merten, 2022. "Combi-seq for multiplexed transcriptome-based profiling of drug combinations using deterministic barcoding in single-cell droplets," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    8. Oliver J. Ziff & Jacob Neeves & Jamie Mitchell & Giulia Tyzack & Carlos Martinez-Ruiz & Raphaelle Luisier & Anob M. Chakrabarti & Nicholas McGranahan & Kevin Litchfield & Simon J. Boulton & Ammar Al-C, 2023. "Integrated transcriptome landscape of ALS identifies genome instability linked to TDP-43 pathology," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    9. Zhaoyu Xue & Hongwen Xuan & Kin Lau & Yangzhou Su & Marc Wegener & Kuai Li & Lisa Turner & Marie Adams & Xiaobing Shi & Hong Wen, 2025. "Expression of ENL YEATS domain tumor mutations in nephrogenic or stromal lineage impairs kidney development," Nature Communications, Nature, vol. 16(1), pages 1-22, December.
    10. Lisa Veghini & Davide Pasini & Rui Fang & Pietro Delfino & Dea Filippini & Christian Neander & Caterina Vicentini & Elena Fiorini & Francesca Lupo & Sabrina L. D’Agosto & Carmine Carbone & Antonio Ago, 2024. "Differential activity of MAPK signalling defines fibroblast subtypes in pancreatic cancer," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    11. Shuangsang Fang & Mengyang Xu & Lei Cao & Xiaobin Liu & Marija Bezulj & Liwei Tan & Zhiyuan Yuan & Yao Li & Tianyi Xia & Longyu Guo & Vladimir Kovacevic & Junhou Hui & Lidong Guo & Chao Liu & Mengnan , 2025. "Stereopy: modeling comparative and spatiotemporal cellular heterogeneity via multi-sample spatial transcriptomics," Nature Communications, Nature, vol. 16(1), pages 1-19, December.
    12. Zhuoxuan Li & Tianjie Wang & Pentao Liu & Yuanhua Huang, 2023. "SpatialDM for rapid identification of spatially co-expressed ligand–receptor and revealing cell–cell communication patterns," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    13. David R. Ghasemi & Konstantin Okonechnikov & Anne Rademacher & Stephan Tirier & Kendra K. Maass & Hanna Schumacher & Piyush Joshi & Maxwell P. Gold & Julia Sundheimer & Britta Statz & Ahmet S. Rifaiog, 2024. "Compartments in medulloblastoma with extensive nodularity are connected through differentiation along the granular precursor lineage," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    14. Qilin Zhang & Ziyan Xu & Rui Han & Yunzhi Wang & Zhen Ye & Jiajun Zhu & Yixin Cai & Fan Zhang & Jiangyan Zhao & Boyuan Yao & Zhaoyu Qin & Nidan Qiao & Ruofan Huang & Jinwen Feng & Yongfei Wang & Wenti, 2024. "Proteogenomic characterization of skull-base chordoma," Nature Communications, Nature, vol. 15(1), pages 1-32, December.
    15. Zoe Piran & Mor Nitzan, 2024. "SiFT: uncovering hidden biological processes by probabilistic filtering of single-cell data," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    16. Sabrina Schütz & Llorenç Solé-Boldo & Carlota Lucena-Porcel & Jochen Hoffmann & Alexander Brobeil & Anke S. Lonsdorf & Manuel Rodríguez-Paredes & Frank Lyko, 2023. "Functionally distinct cancer-associated fibroblast subpopulations establish a tumor promoting environment in squamous cell carcinoma," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    17. Hao Li & Meng-Jie Zhang & Boxin Zhang & Wen-Ping Lin & Shu-Jin Li & Dian Xiong & Qing Wang & Wen-Da Wang & Qi-Chao Yang & Cong-Fa Huang & Wei-Wei Deng & Zhi-Jun Sun, 2025. "Mature tertiary lymphoid structures evoke intra-tumoral T and B cell responses via progenitor exhausted CD4+ T cells in head and neck cancer," Nature Communications, Nature, vol. 16(1), pages 1-20, December.
    18. Kaja Kostyrko & Marta Román & Alex G. Lee & David R. Simpson & Phuong T. Dinh & Stanley G. Leung & Kieren D. Marini & Marcus R. Kelly & Joshua Broyde & Andrea Califano & Peter K. Jackson & E. Alejandr, 2023. "UHRF1 is a mediator of KRAS driven oncogenesis in lung adenocarcinoma," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    19. Chen Ni & Xiaohan Lou & Xiaohan Yao & Linlin Wang & Jiajia Wan & Xixi Duan & Jialu Liang & Kaili Zhang & Yuanyuan Yang & Li Zhang & Chanjun Sun & Zhenzhen Li & Ming Wang & Linyu Zhu & Dekang Lv & Zhih, 2022. "ZIP1+ fibroblasts protect lung cancer against chemotherapy via connexin-43 mediated intercellular Zn2+ transfer," Nature Communications, Nature, vol. 13(1), pages 1-20, December.
    20. Zachary V. Johnson & Brianna E. Hegarty & George W. Gruenhagen & Tucker J. Lancaster & Patrick T. McGrath & Jeffrey T. Streelman, 2023. "Cellular profiling of a recently-evolved social behavior in cichlid fishes," Nature Communications, Nature, vol. 14(1), pages 1-19, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-61214-1. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.