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

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, Katherine J. Young, Paul G. Murray, Christopher Park, Boris Reizis and Vinodh Pillai ()
Additional contact information
David Smith: Children’s Hospital of Philadelphia Research Institute
Anna Eichinger: New York University Grossman School of Medicine
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
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

Nature Communications, 2025, vol. 16, issue 1, 1-14

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-61214-1

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