Inflammatory stromal and T cells mediate human bone marrow niche remodeling in clonal hematopoiesis and myelodysplasia

Karin D. Prummel, Kevin Woods, Maksim Kholmatov, Eric C. Schmitt, Evi P. Vlachou, Mayssa Labyadh, Rebekka Wehner, Gereon Poschmann, Kai Stühler, Susann Winter, Uta Oelschlaegel, Manja Wobus, Logan S. Schwartz, Pedro L. Moura, Eva Hellström-Lindberg, Krishnaraj Rajalingam, Matthias Theobald, Jennifer J. Trowbridge, Clémence Carron, Thierry Jaffredo, Marc Schmitz, Uwe Platzbecker, Judith B. Zaugg () and Borhane Guezguez ()
Additional contact information
Karin D. Prummel: European Molecular Biology Laboratory (EMBL)
Kevin Woods: University Medical Center of of the Johannes Gutenberg University
Maksim Kholmatov: European Molecular Biology Laboratory (EMBL)
Eric C. Schmitt: University Medical Center of of the Johannes Gutenberg University
Evi P. Vlachou: European Molecular Biology Laboratory (EMBL)
Mayssa Labyadh: Adaptation and Ageing
Rebekka Wehner: TU Dresden
Gereon Poschmann: Heinrich Heine University Düsseldorf
Kai Stühler: Heinrich Heine University Düsseldorf
Susann Winter: TU Dresden
Uta Oelschlaegel: TU Dresden
Manja Wobus: DKFZ
Logan S. Schwartz: The Jackson Laboratory
Pedro L. Moura: Karolinska Institute
Eva Hellström-Lindberg: Karolinska Institute
Krishnaraj Rajalingam: University Medical Center of the Johannes Gutenberg University
Matthias Theobald: University Medical Center of of the Johannes Gutenberg University
Jennifer J. Trowbridge: The Jackson Laboratory
Clémence Carron: Adaptation and Ageing
Thierry Jaffredo: Adaptation and Ageing
Marc Schmitz: TU Dresden
Uwe Platzbecker: TU Dresden
Judith B. Zaugg: European Molecular Biology Laboratory (EMBL)
Borhane Guezguez: University Medical Center of of the Johannes Gutenberg University

Nature Communications, 2025, vol. 16, issue 1, 1-25

Abstract: Abstract Somatic mutations in hematopoietic stem/progenitor cells (HSPCs) can lead to clonal hematopoiesis of indeterminate potential (CHIP) and progression to myelodysplastic syndromes (MDS). Using single-cell and anatomical profiling of a large cohort of human bone marrow (BM), we show that the HSPC BM niche in CHIP and MDS is undergoing inflammatory remodeling. This includes loss of CXCL12⁺ adipogenic stromal cells and the emergence of a distinct population of inflammatory mesenchymal stromal cells (iMSCs), which arise in CHIP and become more prevalent in MDS. Functional studies in primary BM HSPC-MSC co-cultures reveals that healthy aged and CHIP HSPCs activate stromal support, while MDS HSPCs fail to do so. In contrast, MDS blasts further suppress HSPC support and trigger inflammation, indicating disease-stage-specific stromal disruption. In parallel, we show that iMSCs retain partial support and angiogenic potential in MDS, coinciding with expanded BM vasculature. Additionally, we identify IFN-responsive T cells that preferentially interact with iMSCs, potentially reinforcing local inflammation. These findings position iMSCs as central mediators of early BM niche dysfunction and potential therapeutic targets for intercepting pre-malignant hematopoiesis.

Date: 2025
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DOI: 10.1038/s41467-025-65803-y

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