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Self-Assembling Hematopoietic Niche on a Chip: Single Cell Sequencing

ABSTRACT: (Single Cell Sequencing Data) Here we present an integrative, bottom-up approach towards emulating the human bone marrow in vitro. Our method harnesses the regenerative capacity of adult stem cells to self-assemble a complex, specialized microenvironment of human hematopoietic stem cells (HSCs) in a vascularized three-dimensional microphysiological system. Through flow cytometry and single-cell transcriptomic interrogation, we show that the microengineered niche can reconstitute HSC self-renewal, multilineage hematopoiesis, and complex ligand-receptor signaling pathways of the native human marrow. The ability of our model to generate functionally mature myeloid cells also makes it possible to mimic the key physiological processes of innate immunity including neutrophil chemotaxis and intravascular mobilization. To demonstrate the advanced application of the bone marrow-on-a-chip, we present i) a specialized model of bone marrow ablation by proton beam radiotherapy and ii) a multiorgan model of innate immune response against bacterial lung infection. This work advances our ability to reconstruct, probe, and deconvolve the complexity of the bone marrow niche, and may enable new capabilities to model human hematopoiesis and immunity for biomedical and pharmaceutical applications.

ORGANISM(S): Homo sapiens

PROVIDER: GSE162426 | GEO | 2023/11/25

REPOSITORIES: GEO

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Self-Assembling Hematopoietic Niche on a Chip: Bulk sequencing to investigate effect of proton radioablation

Project description:(Radiation Experiments: bulk sequencing data) Here we present an integrative, bottom-up approach towards emulating the human bone marrow in vitro. Our method harnesses the regenerative capacity of adult stem cells to self-assemble a complex, specialized microenvironment of human hematopoietic stem cells (HSCs) in a vascularized three-dimensional microphysiological system. Through flow cytometry and single-cell transcriptomic interrogation, we show that the microengineered niche can reconstitute HSC self-renewal, multilineage hematopoiesis, and complex ligand-receptor signaling pathways of the native human marrow. The ability of our model to generate functionally mature myeloid cells also makes it possible to mimic the key physiological processes of innate immunity including neutrophil chemotaxis and intravascular mobilization. To demonstrate the advanced application of the bone marrow-on-a-chip, we present i) a specialized model of bone marrow ablation by proton beam radiotherapy and ii) a multiorgan model of innate immune response against bacterial lung infection. This work advances our ability to reconstruct, probe, and deconvolve the complexity of the bone marrow niche, and may enable new capabilities to model human hematopoiesis and immunity for biomedical and pharmaceutical applications.

2023-11-25 | GSE162428 | GEO

Embryonic myeloid cells orchestrate niche cell homeostasis critical for the establishment of the definitive HSC pool [II]

Project description:The lifelong replenishment of blood cells relies on the function of definitive HSCs that migrate to the bone marrow during development. This process is tightly controlled by the bone marrow microenvironment. Embryonic macrophages emerge before the onset of definitive hematopoiesis, seed into discrete tissues and contribute to specialized resident macrophages throughout life. However, the functional impact of embryonic macrophages on HSCs or the niche remains unknown. Here, by taking advantage of a lineage tracer mouse tool we show that bone marrow macrophages consist of two ontogenetically distinct cell populations from embryonic and adult hematopoiesis. Mice lacking embryonic myeloid cells have decreased HSC numbers in the bone marrow accompanied by an increase of stem cells in the liver of neonate mice. The emergence of HSCs from embryonic sources is unperturbed because pre-HSC and HSC numbers are normal, suggesting a key role for embryo-derived myeloid cells in orchestrating HSC trafficking around birth. We show here that the establishment of a normal cellular niche space in the bone marrow critically depends on embryonic myeloid cells that are important for the development of mesenchymal stromal cells, but not other non-hematopoietic niche cells, providing evidence for a specific role for embryo-derived myeloid cells in the establishment of a normal niche environment pivotal for HSC homing.

2024-05-01 | GSE265965 | GEO

Embryonic myeloid cells orchestrate niche cell homeostasis critical for the establishment of the definitive HSC pool

2024-04-30 | GSE265827 | GEO

Cardiovascular disease perturbs the vascular hematopoietic stem cell niche

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.

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Bone marrow adipocytes fuel emergency hematopoiesis

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Exercise instructs hematopoietic progenitor cells and reduces chronic leukocytosis [RNA-seq]

Project description:Physical activity modulates communication between fat and the stromal hematopoietic bone marrow niche, leading to changes in hematopoiesis, reduced leukocyte levels and protection from cardiovascular disease.

2019-10-31 | GSE124799 | GEO

The niche for extramedullar hematopoiesis in the spleen

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

Bone marrow niche

Project description:Bone marrow niche

| PRJNA429031 | ENA

Characterization of Human Bone Marrow Niches with Metabolome and Transcriptome Profiling

Project description:The hematopoietic niches in bone marrow (BM) are specialized compartments working in harmony to regulate all the steps of the hematopoiesis cascade. Little is known about how BM niches in healthy humans. Therefore, we investigated the presence of different niches in healthy human BM using comparative omic technologies (Metabolomic and transcriptomic). We sequenced and comparative analyzed mRNA samples of human bone marrow mesenchymal stem cells (MSCs) to generate the gene expression profiles of these cells which obtained from two anatomically different BM regions (R1 and R2).

2021-03-01 | GSE145008 | GEO

MLKL preserves the splenic microenvironment to repress hematopoiesis during atherosclerosis

Project description:Dysregulation of the hematopoietic niche during hyperlipidemia facilitates pathologic leukocyte production, driving atherogenesis. While definitive hematopoiesis primarily occurs in the bone marrow, during atherosclerosis this also occurs in the spleen. Cells of the bone marrow niche, in particular endothelial cells, have been studied in atherosclerosis, while little is known about how splenic endothelial cells respond to the atherogenic environment. Here we show unique dysregulated pathways in splenic compared to bone marrow endothelial cells during atherosclerosis, including perturbations of lipid metabolism and endocytic trafficking pathways. As part of this response, we identified MLKL as a repressor of splenic, but not bone marrow, myelopoiesis. Silencing MLKL in splenic endothelial cells results in inefficient endosomal trafficking and lipid accumulation, ultimately promoting the production of myeloid cells that participate in plaque development. These studies identify endocytic trafficking by MLKL as a key mechanism of splenic endothelial cell maintenance, splenic hematopoiesis, and subsequently atherosclerosis.

2024-03-29 | GSE216341 | GEO

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