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Lymphoma B cells remodel bone marrow stromal cell network into extracellular matrix-producing cancer-associated fibroblasts (scRNAseq)

ABSTRACT: Bone marrow (BM) involvement is a common feature of lymphomas deriving from germinal-center B cells and is associated with a bad prognosis. In particular, follicular lymphoma (FL) infiltrates the BM in 70% of cases, in association with a remodeling of surrounding tumor microenvironment. Analysis of in vitro-expanded FL mesenchymal stromal cells (MSCs) revealed an extensive alteration of BM stromal cell phenotypic, transcriptomic, and functional profiles. However, the mechanisms supporting the direct interplay between lymphoma B cells and their permissive stromal niche in situ have not been yet identified. In the current work, we identified in the BM milieu of FL patients a deregulation of soluble and extracellular matrix (ECM) components reflecting inflammation and ectopic differentiation into lymphoid-like stromal cells. We reproduced the same alterations in a murine model of lymphoma B-cell xenograft where a scRNAseq approach identified LepRpos MSCs as specifically and progressively reprogramed by tumor B-cell invasion. Analysis of FL BM collected before and after treatment confirmed that BM niche was partly dependent on the continuous contact with tumor B cells. Altogether, this work shed new lights on the kinetic and mechanisms of BM stromal niche reshaping in B-cell lymphoma.

ORGANISM(S): Mus musculus

PROVIDER: GSE271805 | GEO | 2025/07/23

REPOSITORIES: GEO

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Project description:Haematopoietic stem cells (HSCs) reside in bone marrow (BM) niches where they are maintained to replenish all blood cell lineages throughout life. Among the constituents of the murine HSC niches, various cell types such as CXCL12-abundant reticular (CAR) cells, Nestin-GFP+ perivascular cells, leptin receptor (LepR)+ cells, endothelial cells, osteoblasts, sympathetic nerves, macrophages and megakaryocytes in the BM have been proposed to contribute to HSC niche activity. When niche cells are removed from their natural habitat, the ability to maintain HSCs ex vivo is markedly diminished. Mesenchymal-derived stromal cells (MSCs) identified by Nestin-GFP express high levels of niche factors in vivo, but their expression is downregulated rapidly upon culture, suggesting that alterations in transcriptional rewiring may contribute to the reduced HSC maintenance potential. We found that the enforced expression of 5 genes (Klf7, Ostf1, Xbp1, Irf3 and Irf7) markedly restored HSC niche function in cultured BM-derived MSCs. These revitalized MSCs (rMSCs) exhibited boosted synthesis of HSC niche factors while retaining their mesenchymal lineage differentiation capacity. By contrast to HSCs co-cultured with control MSCs, HSCs expanded with rMSCs showed significantly higher repopulation capacity. To evaluate to what extent rMSCs are reprogrammed toward freshly isolated MSCs, we compared, by RNA-seq analysis, the transcriptome of freshly sorted CD45(-) Ter119(-) CD31(-) Scf-GFP(-) cells, CD45(-) Ter119(-) CD31(-) Scf-GFP(+) cells, rMSCs and control vector-transduced stroma. HSC niche-associated genes were highly expressed in both native Scf-GFP(+) stromal cells and rMSCs compared to the Scf-GFP cell fraction and control MSCs. With the motif analysis of ATAC-seq data, we found that myocyte enhancer factor 2c (Mef2c) is one of the key factor in the revitalization of MSCs. These results suggest that rMSC may provide a promising platform for curative transplantation therapies.

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Lymphoma B cells remodel bone marrow stromal cell network into extracellular matrix-producing cancer-associated fibroblasts (scRNAseq)

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