Comprehensive spatial profiling of the spleen in human myelofibrosis [ST_Visium]
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE332563 | GEO | 2026/06/29
REPOSITORIES: GEO
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Project description: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 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. Macrophage- and megakaryocyte-derived signals activate complement and induce TNFα, TGF-β, extracellular matrix, and Thbs1 programs in reticular cells.
2026-06-29 | GSE332562 | GEO
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.
2026-07-03 | GSE337447 | GEO
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
Project description:Myelofibrosis is a severe myeloproliferative neoplasm characterised by increased numbers of abnormal bone marrow megakaryocytes that induce fibrosis, destroying the hematopoietic microenvironment. To determine the cellular and molecular basis for aberrant megakaryopoiesis in myelofibrosis, we performed single-cell transcriptome profiling of 135,929 CD34+Lineage- hematopoietic stem/progenitor cells (HSPCs), single-cell proteomics, genomics and functional assays. We identified a bias towards megakaryocyte differentiation apparent from early multipotent stem cells in myelofibrosis and associated aberrant molecular signatures. A sub-fraction of myelofibrosis megakaryocyte progenitors (MkP) were transcriptionally similar to healthy-donor MkP but the majority were disease-specific, with distinct populations expressing fibrosis- and proliferation-associated genes. Mutant-clone HSPCs showed increased expression of megakaryocyte-associated genes compared to wild-type HSPCs, and we provide early validation of G6B as a potential immunotherapy target. Our study paves the way for selective targeting of the myelofibrosis clone and illustrates the power of single-cell multi-omics to discover tumor-specific therapeutic targets and mediators of tissue fibrosis.
2020-05-07 | GSE144568 | GEO
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.
2020-06-30 | GSE131593 | GEO
Project description:The vascular lining cells in the human spleens include littoral cells (LCs) and other splenic vascular endothelial cells (SVECs). LCs that comprise about 30 percent of the splenic red pulp are specialzed endothelial cells distinct from SVECs. They line the splenic sinusoids and function as the filters and scavengers for senescent or altered red blood cells. Patients with advanced forms of myelofibrosis (MF) often develope extramedullary hematopoiesis in the spleen.Vascular lining cells within MF spleens are thought to serve as a supportive microenvironment for MF hematopoietic cells. In this study we isolated MF and normal LCs and SVECs from human spleens using immunostaining and flow cytometric sorting and used microarrays to analyze the underling mechanism of LCs' unique functions that distinguish them from SVECs, and the properties of MF LCs and SVECs and their contributions to the microenvironment of MF spleens.
2018-05-30 | GSE106532 | GEO
Project description:We report the transcriptome of subsets of mouse splenic mesenchymal reticular cells and lymph node reticular cells obtained from healthy Ccl19-cre x R26R-EYFP mice on a C57BL/6 background. We also examine splenic reticular cells from these mice infected with lymphocytic choriomeningitis virus (LCMV) strain Armstrong (acute infection) or strain Clone 13 (chronic infection). Subsets of CD45- CD31- Ter119- reticular cells were analyzed including PDPN+ T zone reticular cells (TRC) and MAdCAM-1+ marginal reticular cells (MRC) from spleen and lymph nodes. Additionally from the spleen we analyzed PDPN+ CD140a- cells, PDPN+ EYFP- cells, and EYFP+ red pulp reticular cells (RPRC) in healthy mice. We analyzed TRC, MRC, PDPN+ EYFP- cells, and EYFP+ RPRC from mice infected with LCMV Armstrong or LCMV Clone-13 on day 8 or on day 30 after infection. Our study represents the first detailed analysis of splenic reticular cell transcriptomes in healthy and LCMV-infected mice, with biologic replicates, generated by RNA-sequencing. We find substantial differential gene expression across subsets of splenic and lymph node reticular cells. We reveal significant changes in gene expression induced after virus infection that differ markedly with disease.
2022-01-09 | GSE171124 | GEO
Project description:Primary myelofibrosis (PMF) is a Myeloproliferative Neoplasm (MPN) characterized by megakaryocyte hyperplasia, progressive bone marrow fibrosis, extramedullary hematopoiesis and transformation to Acute Myeloid Leukemia (AML). Beginning in early 2005, a number of novel mutations involving JAK2, CALR, MPL, TET2, ASXL1, DNMT3a, CBL, IDH1 and IDH2 have been described in MPNs, depicting a really complex genomic landscape for MPNs. To shed light on the genomic lesions that can contribute to disease phenotype and/or development, we integrated gene expression and copy number signals and identified several genomic abnormalities leading to a concordant alteration in gene expression levels. In particular, copy number gain in the polyamine oxidase (PAOX) gene locus is accompanied by a coordinated transcriptional up-regulation in PMF patients. Inhibition of PAOX resulted in rapid cell death in PMF progenitor cells, but not in normal cells, suggesting that PAOX inhibition could represent a therapeutic strategy to selectively target PMF cells without affecting normal hematopoietic cells’ survival. Moreover, copy number loss in the chromatin modifier HMGXB4 gene correlates with a concomitant transcriptional down-regulation in PMF patients. Interestingly, silencing of HMGXB4 induces megakaryocyte differentiation, while inhibiting erythroid development, in human hematopoietic stem/progenitor cells. These results highlight a previously un-reported, yet potentially interesting role of HMGXB4 in the hematopoietic system suggesting that genomic and transcriptional imbalances of HMGXB4 could contribute to the aberrant expansion of the megakaryocytic lineage that characterize PMF patients. In this study, the authors take advantage of the integrative analysis of gene expression and copy number data to identify the concordant gain/up-regulation of the polyamine oxidase PAOX and the loss/down-regulation of the chromatin modifier HMGXB4. This work sheds light on the influence of genomic abnormalities on gene expression regulation in PMF CD34+ cells and on their contribution to specific features of PMF, such as a hyperplastic megakaryopoiesis.
2018-05-21 | GSE69161 | GEO
Project description:This study investigates the role of translocator protein (TSPO) in splenic immune responses following sepsis using a mouse cecal ligation and puncture (CLP) model. Bulk RNA sequencing of spleen tissue collected 17 days after sham or CLP surgery revealed that TSPO deficiency promotes splenomegaly characterized by red pulp expansion, enhanced erythropoiesis, and reduced immune responses. Gene expression and deconvolution analyses indicated decreased lymphocyte signatures and increased erythroblast and megakaryocyte signatures in TSPO knockout mice. These findings suggest that TSPO plays a critical role in maintaining splenic immune homeostasis after sepsis.
2026-04-27 | GSE329160 | GEO
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)
2015-08-01 | E-GEOD-71288 | biostudies-arrayexpress