Single cell analysis in the adult bone marrow vascular niche after Vegfc deletion
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ABSTRACT:
PROVIDER: PRJNA603585 | ENA |
REPOSITORIES: ENA
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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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Project description:While colorectal cancer liver metastasis (CRCLM) is major cause of death of colorectal cancer, the mechanism of intrahepatic dissemination (trans-lymphatic metastasis) is not fully elucidated. Lymphangiogenesis can be the mechanism of the dissemination, but there are few evidences to prove it. In this study, we attempted to clarify the mechanism using syngeneic murine CRCLM model, especially focusing on vascular endothelial growth factor C (VEGFC), a promoter of lymphangiogenesis. We confirmed that 1) intrahepatic metastasis of CRCLM via lymphatic vessels was seen and lymphangiogenesis was upregulated in the CRCLM-bearing liver, 2) the degree of lymphangiogenesis and CRCLM was significantly correlated with the expression of VEGFC in colorectal cancer (CRC) cells and 3) macrophage inflammatory protein-1α (MIP-1α) was released from CRC cells under the stimulation of VEGFC and induced migration of immature bone marrow derived cells into the liver and differentiation into macrophage, which promoted dissemination of CRCLM. These findings suggest the possibility of therapeutic strategy targeting VEGFC / MIP-1α for diminishing CRCLM. In conclusion, VEGFC in CRC cells promoted trans-lymphatic metastasis of CRCLM by upregulation of lymphangiogenesis directly and indirectly via induction of macrophages derived from bone marrow cells.
2018-09-30 | GSE113235 | GEO
Project description:Fate decisions of haematopoietic stem cells (HSCs) to self-renew or differentiate in response to various demands are finely tuned by specialized microenvironments called “niches” in the bone marrow. Recent studies suggest that arterioles and sinusoids accompanied with distinct stromal cells marked by nerve/glial antigen 2 (NG2) and leptin receptor (LepR), compose distinct niches regulating quiescence and proliferation of HSCs, respectively. However, it remains unknown how the distinct niche cells differentially regulate the HSC functions. Here we show that effects of cytokines regulating HSC functions are dependent on the producing cell sources. Deletion of chemokine C-X-C motif ligand 12 (CXCL12) in NG2-cre targeted cells, which exclusively overlap with Nestin-GFP (Nes-GFP)+ stromal cells associated with arterioles and sinusoids, resulted in a robust reductions of HSCs in the bone marrow and massive mobilization. Deletion of CXCL12 from arteriolar NG2+ vascular smooth muscle cells caused a significant decrease of HSCs and altered HSC location in the marrow, while CXCL12 depletion from sinusoidal LepR+ cells did not reduce HSC numbers in the bone marrow. By contrast, deletion of stem cell factor (SCF) in LepR+ cells led to significant reductions in HSC numbers whereas SCF deletion in arteriolar NG2+ cells showed no effect on HSC numbers in the marrow. These results uncover the distinct contributions of cytokines derived from perivascular cells in separate vascular niches for HSC maintenance and mobilization. We sought to obtain comprehensive understanding of differences between peri-arteriolar and peri-sinusoidal niche cells by the present RNA-seq analysis.
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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.
2023-11-04 | GSE169267 | GEO
Project description:The bone marrow (BM) niche comprised of BM endothelial cells (BMECs) and LepR+ mesenchymal stromal cells (MSCs), plays a critical role in preserving the fitness of hematopoietic stem cells (HSCs). Aging is associated with defects in the BM niche that impair their ability to support HSC activity. However, mechanisms underlying age-related defects in the BM niche remain poorly understood. In this study, we identify BM niche derived Netrin-1 (NTN1) as a critical regulator of BM niche cell fitness during aging. Conditional deletion of NTN-1 specifically within BM MSCs or BMECs of young mice resulted in premature aging phenotypes within the BM niche including increased vascular leakiness, hypoxia, DNA damage and adiposity. On the other hand, supplementation of aged mice with NTN1 resulted in restoration of these hallmark niche defects and a rejuvenation of HSC activity. Mechanistically, we identify NTN1 as a critical regulator of DNA Damage Response (DDR) within BM niche cells and HSCs. In this experiment, RNA Seq analysis was performed on BM MSCs and BMECs following conditional deletion of NTN1 within BMECs or MSCs to characterize transcriptional alterations within BM niche cells resulting from a deficiency of niche derived NTN1.
2023-04-14 | GSE227147 | GEO
Project description:The bone marrow (BM) niche comprised of BM endothelial cells (BMECs) and LepR+ mesenchymal stromal cells (MSCs), plays a critical role in preserving the fitness of hematopoietic stem cells (HSCs). Aging is associated with defects in the BM niche that impair their ability to support HSC activity. However, mechanisms underlying age-related defects in the BM niche remain poorly understood. In this study, we identify BM niche derived Netrin-1 (NTN1) as a critical regulator of BM niche cell fitness during aging. Conditional deletion of NTN-1 specifically within BM MSCs or BMECs of young mice resulted in premature aging phenotypes within the BM niche including increased vascular leakiness, hypoxia, DNA damage and adiposity. On the other hand, supplementation of aged mice with NTN1 resulted in restoration of these hallmark niche defects and a rejuvenation of HSC activity. Mechanistically, we identify NTN1 as a critical regulator of DNA Damage Response (DDR) within BM niche cells and HSCs. In this experiment, RNA Seq analysis was performed on BM MSCs and BMECs following conditional deletion of NTN1 within BMECs or MSCs to characterize transcriptional alterations within BM niche cells resulting from a deficiency of niche derived NTN1.
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