Spatial profiling of the spleen in mouse and human myelofibrosis reveals complement-driven immune-stromal interactions as a therapeutic target
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.
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BibTeX
@article{dugue2026spatial,
title = {{Spatial profiling of the spleen in mouse and human myelofibrosis reveals complement-driven immune-stromal interactions as a therapeutic target}},
author = {Bérénice Dugué and Pia Wanner and Mayra L Ruiz Tejada Segura and Mohamed Saad and Lucas Greven and Katrin Götz and Carmen Schalla and Stijn Fuchs and Gerjanne Vroeg In de Wei and Hélène F E Gleitz and Anna Katharina Galyga and Jessica Ellen Pritchard and Tobias Schlangen and Niklas Lutterbach and Salim Atakhanov and Lina Schmidt and Marie Parrens and Armelle Peyrat and Damien Luque Paz and Marie-Christine Copin and Alexandre Guy and Victor-Emmanuel Brett and Olivier Mansier and Susanne Schmitz and Paul Wanek and Bella Banjanin and Stephani Schmitz and Martina Crysandt and Marian C Clahsen-van Groningen and Konnie M Hebeda and Sascha Dietrich and Harald Voehringer and Matthias Meyer-Bender and Kristin Séré and Chloé James and Adam Benabid and Ivan Costa and Charles Dussiau and Rebekka K Schneider},
journal = {Cell Stem Cell},
year = {2026},
month = sep,
doi = {10.1016/j.stem.2026.07.012},
url = {https://nantes-universite.hal.science/hal-05745596v1},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - Spatial profiling of the spleen in mouse and human myelofibrosis reveals complement-driven immune-stromal interactions as a therapeutic target
AU - Bérénice Dugué
AU - Pia Wanner
AU - Mayra L Ruiz Tejada Segura
AU - Mohamed Saad
AU - Lucas Greven
AU - Katrin Götz
AU - Carmen Schalla
AU - Stijn Fuchs
AU - Gerjanne Vroeg In de Wei
AU - Hélène F E Gleitz
AU - Anna Katharina Galyga
AU - Jessica Ellen Pritchard
AU - Tobias Schlangen
AU - Niklas Lutterbach
AU - Salim Atakhanov
AU - Lina Schmidt
AU - Marie Parrens
AU - Armelle Peyrat
AU - Damien Luque Paz
AU - Marie-Christine Copin
AU - Alexandre Guy
AU - Victor-Emmanuel Brett
AU - Olivier Mansier
AU - Susanne Schmitz
AU - Paul Wanek
AU - Bella Banjanin
AU - Stephani Schmitz
AU - Martina Crysandt
AU - Marian C Clahsen-van Groningen
AU - Konnie M Hebeda
AU - Sascha Dietrich
AU - Harald Voehringer
AU - Matthias Meyer-Bender
AU - Kristin Séré
AU - Chloé James
AU - Adam Benabid
AU - Ivan Costa
AU - Charles Dussiau
AU - Rebekka K Schneider
PY - 2026
DA - 2026/09/10
JO - Cell Stem Cell
DO - 10.1016/j.stem.2026.07.012
UR - https://nantes-universite.hal.science/hal-05745596v1
AB - 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.
SN - 1934-5909
SN - 1875-9777
ER -