Inflammation perturbs hematopoiesis by remodeling specific compartments of the bone marrow niche
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PROVIDER: PRJNA1158854 | ENA |
REPOSITORIES: ENA
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Project description:Hematopoietic stem and progenitor cells (HSPC) are regulated by interactions with stromal cells in the bone marrow (BM) cavity, which can be segregated into two spatially defined central marrow (CM) and endosteal (Endo) compartments. However, the importance of this spatial compartmentalization for BM responses to inflammation and neoplasia remains largely unknown. Here, we extensively validate a combination of scRNA-seq profiling and matching flow cytometry isolation that reproducibly identifies 7 key CM and Endo populations across mouse strains and accurately surveys both niche locations. We demonstrate that different perturbations exert specific effects on different compartments, with type I interferon responses causing CM mesenchymal stromal cells to adopt an inflammatory phenotype associated with overproduction of chemokines modulating local monocyte dynamics in the surrounding microenvironment. Our results provide a comprehensive method for molecular and functional stromal characterization and highlight the importance of altered stomal cell activity in regulating hematopoietic responses to inflammatory challenges.
2025-10-27 | GSE276784 | GEO
Project description: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.
2025-09-29 | GSE309534 | GEO
Project description: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.
2025-09-29 | GSE309540 | GEO
Project description: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.
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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)
2015-08-01 | E-GEOD-71288 | biostudies-arrayexpress
Project description:Hematopoiesis advances cardiovascular disease by generating inflammatory leukocytes that attack the arteries, heart and brain. While it is well documented that the bone marrow niche regulates hematopoietic stem cell proliferation and hence the systemic leukocyte pool, it is less clear how cardiovascular disease affects the vasculature forming this niche. Here we show that arterial hypertension, atherosclerosis and myocardial infarction alter the anatomy and function of bone marrow vasculature. Hypertension and atherosclerosis instigated vascular fibrosis, leakage and endothelial dysfunction in the bone marrow. Myocardial infarction induced vascular leakage and bone marrow angiogenesis via Vegf signaling. Endothelial cell-specific deletion of the Vegf receptor 2 limited emergency hematopoiesis after myocardial infarction, indicating that new vasculature supports higher blood cell production. RNA-sequencing of bone marrow endothelial cells revealed inflammatory gene expression in mice with cardiovascular disease. Endothelial cell-specific deletion of interleukin 6 or versican, which were highly expressed in mice with atherosclerosis or myocardial infarction, respectively, reduced hematopoiesis and systemic myeloid cells. Taken together, cardiovascular disease affects the vascular bone marrow niche, thus influencing hematopoietic stem cell behavior and expanding innate immune cell supply to atherosclerotic plaque and ischemic myocardium. Interrupting this feed back loop may constrain cardiovascular inflammation.
2021-09-27 | GSE144498 | GEO
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