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Comprehensive spatial profiling of the spleen in murine myelofibrosis identifies targetable immune-stromal interactions

ABSTRACT: Splenomegaly is a defining feature of myelofibrosis, yet the contribution of splenic mesenchymal stroma to disease progression remains unclear. We perferomed spatial transcriptomics of murine spleens to map extramedullary hematopoiesis niches. Activated red pulp reticular cells localize near hematopoietic stem and progenitor cells, and early disease shows marginal zone disruption with lymphoid depletion preceding stromal remodeling. Trajectory analyses reveal a shift of reticular cells from hematopoiesis-supportive to inflammatory and pro-fibrotic states driven by macrophage- and megakaryocyte-derived signals that activate complement and induce TNFα, TGF-β, extracellular matrix, and Thbs1 programs. Stromal deletion or pharmacological inhibition of complement component C3 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 a targetable axis in myelofibrosis.

ORGANISM(S): Mus musculus

PROVIDER: GSE337447 | GEO | 2026/07/03

REPOSITORIES: GEO

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Comprehensive single cell RNA profiling of the spleen in murine myelofibrosis identifies targetable immune-stromal interactions

Project description:Splenomegaly is a defining feature of myelofibrosis, yet the contribution of splenic mesenchymal stroma to disease progression remains unclear. We perferomed spatial transcriptomics of murine spleens to map extramedullary hematopoiesis niches. Activated red pulp reticular cells localize near hematopoietic stem and progenitor cells, and early disease shows marginal zone disruption with lymphoid depletion preceding stromal remodeling. Trajectory analyses reveal a shift of reticular cells from hematopoiesis-supportive to inflammatory and pro-fibrotic states driven by macrophage- and megakaryocyte-derived signals that activate complement and induce TNFα, TGF-β, extracellular matrix, and Thbs1 programs. Stromal deletion or pharmacological inhibition of complement component C3 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 a targetable axis in myelofibrosis.

2026-07-01 | GSE336713 | GEO

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Project description:Adult hematopoietic stem cells (HSCs) reside primarily in bone marrow. However, hematopoietic stresses such as myelofibrosis, anemia, pregnancy, infection or myeloablation can mobilize HSCs to the spleen and induce extramedullary hematopoiesis (EMH). While the bone marrow HSC niche has been studied intensively, the EMH niche has received little attention. Here, we systematically assessed the physiological sources of the key niche factors, SCF and CXCL12, in the mouse spleen after EMH induction by cyclophosphamide plus granulocyte colony-stimulating factor, blood loss, or pregnancy. In each case, Scf was expressed by endothelial cells and Tcf21+ stromal cells, primarily around sinusoids in red pulp, while Cxcl12 was expressed by a subset of Tcf21+ stromal cells. EMH induction markedly expanded the Scf-expressing endothelial cells and stromal cells by inducing proliferation. Most splenic HSCs were adjacent to Tcf21+ stromal cells in red pulp. Conditional deletion of Scf from spleen endothelial cells or Scf or Cxcl12 from Tcf21+ stromal cells severely reduced spleen EMH and reduced blood cell counts without affecting bone marrow hematopoiesis. Endothelial cells and Tcf21+ stromal cells thus create the splenic EMH niche, which is necessary for the physiological response to diverse hematopoietic stresses. Unfractionated spleen cells (2 replicates) and FACS-sorted VE-cadherein negative Scf-GFP positive cells (3 replicates)

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Gene expression data of bone marrow mesenchymal stromal cells in myelofibrosis

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Single-cell analyses reveal aberrant pathways for megakaryocyte-biased hematopoiesis in myelofibrosis and identify mutant clone-specific targets

Project description:Myelofibrosis is a severe myeloproliferative neoplasm characterised by increased numbers of abnormal bone marrow megakaryocytes that induce progressive fibrosis, destroying the hematopoietic microenvironment. To determine the cellular and molecular basis for aberrant megakaryopoiesis in myelofibrosis, we performed high-throughput single-cell transcriptome profiling of 50,702 hematopoietic stem/progenitor cells (HSPCs), and single-cell proteomics, genomics and functional assays. We identified an aberrant pathway for direct megakaryocyte differentiation from the earliest stages of hematopoiesis in myelofibrosis and associated aberrant molecular signatures, including surface antigens selectively expressed by JAK2-mutant HSPCs. Myelofibrosis megakaryocyte progenitors were heterogeneous, with distinct expression of fibrosis and proliferation-associated genes and putative therapy targets. We validated the integrin G6B as a promising JAK2-mutant clone-specific surface antigen, warranting further development as an immunotherapeutic target. Our study paves the way for selective immunotherapeutic targeting in myelofibrosis and more broadly illustrates the power of single-cell multi-omics to discover tumor-specific therapeutic targets and mediators of tissue fibrosis.

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