Spatial profiling of the spleen in mouse and human myelofibrosis reveals complement-driven immune-stromal interactions as a therapeutic target
Year: 2026
Type: article
Abstract: Splenomegaly is a defining feature of myelofibrosis, yet the contribution of splenic mesenchymal stroma to disease progression remains unclear. We combined spatial and single-nucleus transcriptomics of patient spleens with spatial and single-cell transcriptomics, as well as imaging analyses, of murine spleens to map extramedullary hematopoiesis niches. Activated red pulp reticular cells localize near hematopoietic stem and progenitor cells, and early disease is characterized by marginal zone disruption with lymphoid depletion preceding stromal remodeling. Trajectory analyses reveal a shift in reticular cells from hematopoiesis-supportive to inflammatory and pro-fibrotic states, driven by macrophage- and megakaryocyte-derived signals that activate complement and induce tumor necrosis factor α (TNF-α), transforming growth factor β (TGF-β), extracellular matrix, and Thbs1 programs. Non-hematopoietic complement component C3 deficiency or pharmacological C3 inhibition suppresses these pathways, restores splenic architecture, and reduces splenomegaly and bone marrow fibrosis. These findings identify complement-dependent stromal reprogramming as a mechanism governing hematopoietic niches and as a targetable axis in myelofibrosis.
Source: Cell stem cell
Authors: Bérénice Dugué, Pia Wanner, Mayra L. Ruiz Tejada Segura, Mohamed Saad, Lucas Greven, Katrin Götz, Carmen Schalla, Stijn Fuchs, Gerjanne Vroeg in de wei, Hélène F.E. Gleitz, Anna Katharina Galyga, Jessica Ellen Pritchard, Tobias Schlangen, Niklas Lutterbach, Salim Atakhanov, Lina Schmidt, Marie Parrens, Armelle Peyrat, Damien Luque Paz, Marie-Christine Copin, Alexandre Guy, Victor-Emmanuel Brett, Olivier Mansier, Susanne Schmitz, Paul Wanek, Bella Banjanin, Stephani Schmitz, Martina Crysandt, Marian C. Clahsen-van Groningen, Konnie M. Hebeda, Sascha Dietrich, Harald Voehringer, Matthias Meyer-Bender, Kristin Séré, Chloé James, Adam Benabid, Ivan Costa, Charles Dussiau, Rebekka K. Schneider
Institutions: Université de Bordeaux, Inserm, Biologie des maladies cardiovasculaires, RWTH Aachen University, Erasmus MC, Centre Hospitalier Universitaire de Bordeaux, Centre National de la Recherche Scientifique, Centre de Recherche en Cancérologie et Immunologie Intégrée Nantes Angers, Centre Hospitalier Universitaire d'Angers, Université d'Angers, Nantes Université, Universitätsklinikum Aachen, Erasmus MC Transplant Institute, Radboud University Medical Center, Düsseldorf University Hospital, Heinrich Heine University Düsseldorf, Heidelberg University, European Molecular Biology Laboratory, German Cancer Research Center, European Molecular Biology Laboratory, Heidelberg Institute for Stem Cell Technology and Experimental Medicine
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $10,400
OpenAlex ID: W7204157419