Vascular niche induction of hematopoietic progenitors from pluripotent stem cells
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PROVIDER: PRJNA271536 | ENA |
REPOSITORIES: ENA
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Project description:Pluripotent stem cells (PSC) represent an alternative source of hematopoietic stem cells (HSCs). Clinical translation is impeded by limited engraftment of human (h)PSC-multipotent progenitor cells (MPP). This barrier suggests that additional cues are required for definitive hematopoiesis. We hypothesized that vascular niche producing Notch ligands Jagged-1 (JAG1) and Delta-like ligand-4 (DLL4) would drive definitive hematopoiesis. To test our hypothesis, hes2 human embryonic stem cells (hESC) 2 and Macaca nemestrina (Mn) iPSC line-7 were differentiated with cytokines ± endothelial cells (EC), which express JAG1 and DLL4. EC co-culture supported emergence of 8-fold more CD34+CD45+ cells compared to co-culture with cytokines ± ECs with JAG1 or DLL4 knockdown. EC-induced cells exhibit Notch activation and express HSC-specific targets of Notch signaling RUNX1 and GATA2. EC-induced PSC-MPP engraft at a higher level in NSG mice compared to cytokine-induced cells (10% >5 months), and selection increased engraftment (30%). Long-term engraftment and the myeloid-to-lymphoid ratio achieved with vascular niche induction is similar to levels achieved for cord blood MPP and up to 20-fold higher than hPSC-MPP engraftment. Our findings identify a previously underappreciated role for endothelial Notch ligands in PSC definitive hematopoiesis and production of long-term engrafting CD34+ cells and suggest they are critical for HSC emergence. Transcriptome sequencing of Macaca nemestrina (Mn) iPSCs
2015-12-31 | E-GEOD-64644 | biostudies-arrayexpress
Project description:Pluripotent stem cells (PSC) represent an alternative source of hematopoietic stem cells (HSCs). Clinical translation is impeded by limited engraftment of human (h)PSC-multipotent progenitor cells (MPP). This barrier suggests that additional cues are required for definitive hematopoiesis. We hypothesized that vascular niche producing Notch ligands Jagged-1 (JAG1) and Delta-like ligand-4 (DLL4) would drive definitive hematopoiesis. To test our hypothesis, hes2 human embryonic stem cells (hESC) 2 and Macaca nemestrina (Mn) iPSC line-7 were differentiated with cytokines ± endothelial cells (EC), which express JAG1 and DLL4. EC co-culture supported emergence of 8-fold more CD34+CD45+ cells compared to co-culture with cytokines ± ECs with JAG1 or DLL4 knockdown. EC-induced cells exhibit Notch activation and express HSC-specific targets of Notch signaling RUNX1 and GATA2. EC-induced PSC-MPP engraft at a higher level in NSG mice compared to cytokine-induced cells (10% >5 months), and selection increased engraftment (30%). Long-term engraftment and the myeloid-to-lymphoid ratio achieved with vascular niche induction is similar to levels achieved for cord blood MPP and up to 20-fold higher than hPSC-MPP engraftment. Our findings identify a previously underappreciated role for endothelial Notch ligands in PSC definitive hematopoiesis and production of long-term engrafting CD34+ cells and suggest they are critical for HSC emergence.
2015-12-31 | GSE64644 | GEO
Project description:Generation of abundant engraftable hematopoietic cells from autologous tissues promises new therapies for hematologic diseases. Differentiation of pluripotent stem cells into hematopoietic cells results in emergence of cells that have poor engraftment potential. To circumvent this hurdle, we have devised a vascular niche model to phenocopy the developmental microenvironment of hemogenic cells thereby enabling direct transcriptional reprogramming of human endothelial cells (ECs) into hematopoietic cells. In this approach, transduction of human umbilical vein ECs (HUVECs) or adult human dermal microvascular ECs (hDMECs) with transcription factors (TFs), FOSB, GFI1, RUNX1, and SPI1 (FGRS) and induction with a instructive vascular niche feeder layer in a xenobiotic- and serum-free microenvironment results in generation of long-term engraftable hematopoietic multilineage progenitors (rEC-HMLPs). The rEC-HMLPs had robust proliferative and multilineage colony forming units (CFU) potential, including granulocytic/monocytic, megakaryocytic, erythroid and lymphoid lineages. When transplanted, hDMEC-derived rEC-HMLPs were capable of long-term multilineage primary and secondary hematopoietic engraftment. A subset of engrafted rEC-HMLPs phenotypically and functionally resembled cord blood cells. By conditionally expressing the FGRS TFs, we further optimized reprogramming of ECs into rEC-HMLPs manifesting features of self-renewing multi-potent progenitor populations (MPPs). Our approach replicates critical aspects of hematopoietic development and essential role of vascular niche induction in orchestrating hematopoietic specification and may prove useful for engineering autologous engraftable hematopoietic cells for treatment of inherited and acquired blood disorders. . Transcriptome sequencing of rEC-HMLPs, hDMECs, HUVECs and other cell types
2014-07-11 | E-GEOD-57662 | biostudies-arrayexpress
Project description:Generation of abundant engraftable hematopoietic cells from autologous tissues promises new therapies for hematologic diseases. Differentiation of pluripotent stem cells into hematopoietic cells results in emergence of cells that have poor engraftment potential. To circumvent this hurdle, we have devised a vascular niche model to phenocopy the developmental microenvironment of hemogenic cells thereby enabling direct transcriptional reprogramming of human endothelial cells (ECs) into hematopoietic cells. In this approach, transduction of human umbilical vein ECs (HUVECs) or adult human dermal microvascular ECs (hDMECs) with transcription factors (TFs), FOSB, GFI1, RUNX1, and SPI1 (FGRS) and induction with a instructive vascular niche feeder layer in a xenobiotic- and serum-free microenvironment results in generation of long-term engraftable hematopoietic multilineage progenitors (rEC-HMLPs). The rEC-HMLPs had robust proliferative and multilineage colony forming units (CFU) potential, including granulocytic/monocytic, megakaryocytic, erythroid and lymphoid lineages. When transplanted, hDMEC-derived rEC-HMLPs were capable of long-term multilineage primary and secondary hematopoietic engraftment. A subset of engrafted rEC-HMLPs phenotypically and functionally resembled cord blood cells. By conditionally expressing the FGRS TFs, we further optimized reprogramming of ECs into rEC-HMLPs manifesting features of self-renewing multi-potent progenitor populations (MPPs). Our approach replicates critical aspects of hematopoietic development and essential role of vascular niche induction in orchestrating hematopoietic specification and may prove useful for engineering autologous engraftable hematopoietic cells for treatment of inherited and acquired blood disorders. .
2014-07-11 | GSE57662 | GEO
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
Project description:Cardiovascular disease perturbs the vascular hematopoietic stem cell niche
| PRJNA603792 | ENA
Project description: Not available
| S-EPMC4362238 | biostudies-literature
Project description:We report transcriptome profiling of bone marrow niche subsets at the population level. Additionally, we report trascriptional changes in lymphoid -primed multipotential progenitors in the absence of vascular DLL4.
2019-04-11 | GSE108885 | GEO
Project description:Mapping the cardiac vascular niche in heart failure
| PRJNA700769 | ENA
Project description:Whereas the cellular basis of the hematopoietic stem cell (HSC) niche in the bone marrow has been characterized, the nature of the fetal liver (FL) niche is not yet elucidated. We show that Nestin+NG2+ pericytes associate with portal vessels, forming a niche promoting HSC expansion. Nestin+NG2+ cells and HSCs scale during development with the fractal branching patterns of portal vessels, tributaries of the umbilical vein. After closure of the umbilical inlet at birth, portal vessels undergo a transition from Neuropilin-1+Ephrin-B2+ artery to EphB4+ vein phenotype, associated with a loss of peri-portal Nestin+NG2+ cells and emigration of HSCs away from portal vessels. These data support a model in which HSCs are titrated against a peri-portal vascular niche with a fractal-like organization enabled by placental circulation. Characterization of the transcriptome of fetal liver and adult bone marrow niche using RNA-seq
2015-12-03 | E-GEOD-72341 | biostudies-arrayexpress