Identification of an Early Unipotent Neutrophil Progenitor with Pro-Tumoral Activity in Mouse and Human Bone Marrow
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA481247 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR7524670.fastq.gz | Fastqsanger.gz | |||
| SRR7524671.fastq.gz | Fastqsanger.gz | |||
| SRR7524662.fastq.gz | Fastqsanger.gz | |||
| SRR7524672.fastq.gz | Fastqsanger.gz | |||
| SRR7524663.fastq.gz | Fastqsanger.gz |
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Project description:Neutrophils are short-lived immune cells that play important roles in a variety of diseases. The oligopotent Granulocyte Monocyte Progenitors (GMP) in the bone marrow give rise to monocytes and all granulocytes. Although several monocyte progenitors have been identified in mouse bone marrow, the unipotent neutrophil progenitors are still not well-defined. Here, we use Cytometry by Time-of-Flight (CyTOF) and Single-cell RNA-Sequencing (scRNA-Seq) methodologies to identify a committed unipotent early-stage neutrophil progenitor in adult mouse bone marrow. Importantly, we also discovered a similar unipotent, committed neutrophil progenitor (hNeP) that is present in healthy human bone marrow. Both mouse and human progenitors demonstrate unipotent neutrophil potency in vivo. Study of the identified mouse (NeP) and human (hNeP) neutrophil progenitors in cancer revealed that both NeP and hNeP significantly increased tumor growth when transferred into murine cancer models, including a humanized model. Further, we discovered that the hNeP was present in the blood of human patients recently diagnosed with melanoma, and could be readily identified by flow cytometry, suggesting that this human neutrophil progenitor could be used as a biomarker for early cancer discovery. The discovery of this early committed unipotent neutrophil progenitor in humans will allow for development of important new therapeutic targets for regulation of neutrophil levels and function in disease, particularly in cancers, where neutrophils play a significant role.
2018-08-28 | GSE117131 | GEO
Project description:Discovery of a Pro-Tumoral Clonogenic Unipotent Neutrophil Progenitor in Mouse and Human Bone Marrow
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Project description:Neutrophils are short-lived immune cells that play important roles in a variety of diseases. The oligopotent Granulocyte Monocyte Progenitors (GMP) in the bone marrow give rise to monocytes and all granulocytes. Although several monocyte progenitors have been identified in mouse bone marrow, the unipotent neutrophil progenitors are still not well-defined. Here, we use Cytometry by Time-of-Flight (CyTOF) and Single-cell RNA-Sequencing (scRNA-Seq) methodologies to identify a committed unipotent early-stage neutrophil progenitor in adult mouse bone marrow. Importantly, we also discovered a similar unipotent, committed neutrophil progenitor (hNeP) that is present in healthy human bone marrow. Both mouse and human progenitors demonstrate unipotent neutrophil potency in vivo. Study of the identified mouse (NeP) and human (hNeP) neutrophil progenitors in cancer revealed that both NeP and hNeP significantly increased tumor growth when transferred into murine cancer models, including a humanized model. Further, we discovered that the hNeP was present in the blood of human patients recently diagnosed with melanoma, and could be readily identified by flow cytometry, suggesting that this human neutrophil progenitor could be used as a biomarker for early cancer discovery. The discovery of this early committed unipotent neutrophil progenitor in humans will allow for development of important new therapeutic targets for regulation of neutrophil levels and function in disease, particularly in cancers, where neutrophils play a significant role.Neutrophils are short-lived immune cells that play important roles in a variety of diseases. The oligopotent Granulocyte Monocyte Progenitors (GMP) in the bone marrow give rise to monocytes and all granulocytes. Although several monocyte progenitors have been identified in mouse bone marrow, the unipotent neutrophil progenitors are still not well-defined. Here, we use Cytometry by Time-of-Flight (CyTOF) and Single-cell RNA-Sequencing (scRNA-Seq) methodologies to identify a committed unipotent early-stage neutrophil progenitor in adult mouse bone marrow. Importantly, we also discovered a similar unipotent, committed neutrophil progenitor (hNeP) that is present in healthy human bone marrow. Both mouse and human progenitors demonstrate unipotent neutrophil potency in vivo. Study of the identified mouse (NeP) and human (hNeP) neutrophil progenitors in cancer revealed that both NeP and hNeP significantly increased tumor growth when transferred into murine cancer models, including a humanized model. Further, we discovered that the hNeP was present in the blood of human patients recently diagnosed with melanoma, and could be readily identified by flow cytometry, suggesting that this human neutrophil progenitor could be used as a biomarker for early cancer discovery. The discovery of this early committed unipotent neutrophil progenitor in humans will allow for development of important new therapeutic targets for regulation of neutrophil levels and function in disease, particularly in cancers, where neutrophils play a significant role.
2018-07-17 | GSE117129 | GEO
Project description:Identification of a CD117+ CD71+ early unipotent neutrophil progenitor population in human bone marrow
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Project description:Neutrophils are short-lived cells that play important roles in both health and disease. Neutrophils and monocytes originate from the granulocyte monocyte progenitor (GMP) in bone marrow; however, unipotent neutrophil progenitors are not well defined. Here, we use cytometry by time of flight (CyTOF) and single-cell RNA sequencing (scRNA-seq) methodologies to identify a committed unipotent early-stage neutrophil progenitor (NeP) in adult mouse bone marrow. Importantly, we found a similar unipotent NeP (hNeP) in human bone marrow. Both NeP and hNeP generate only neutrophils. NeP and hNeP both significantly increase tumor growth when transferred into murine cancer models, including a humanized mouse model. hNeP are present in the blood of treatment-naive melanoma patients but not of healthy subjects. hNeP can be readily identified by flow cytometry and could be used as a biomarker for early cancer discovery. Understanding the biology of hNeP should allow the development of new therapeutic targets for neutrophil-related diseases, including cancer.
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Project description:Neutrophils play critical roles in health and disease. Due to their very short half-life in blood and tissue, neutrophils are constantly replenished by bone marrow progenitors. Thus, a comprehensive understanding of bone marrow neutrophil development is of paramount importance to identify how neutrophil production is altered in disease. Recently, two novel human neutrophil progenitor populations were identified; ‘human neutrophil progenitor’ or ‘hNeP’ (Lin- CD66b+ CD117+ ) and ‘neutrophil precursor’ or ‘preNeu’ (Lin- CD66b+ CD15+ CD49d+ ). How these subsets fit into the neutrophil lineage is unclear. By using mass and flow cytometry, we show that hNeP are a heterogenous population containing a homogeneous progenitor subset termed ‘early neutrophil progenitor’ or ‘eNeP’ (Lin- CD66b+ CD117+ CD71+ ). Surface marker and RNA expression, together with the ability to form colonies in vitro and exclusively produce neutrophils in vivo in humanized NSG-SGM3 mouse transfer experiments indicate that eNeP are hierarchically the ‘earliest’ cells within preNeu. eNeP constitute ~0.14% of human bone marrow neutrophils, while preNeu constitute ~5% of bone marrow neutrophils. Furthermore, we have identified CD71 as a novel neutrophil surface marker associated with distinct early neutrophil developmental stages. Intriguingly, CD71+ characterizes proliferating neutrophils, which are expanded in the blood of melanoma and lung cancer patients and detectable in human lung tumors. Collectively, our findings i) identify CD117+ CD71+ eNeP as an early neutrophil progenitor population, ii) introduce a unified model of human neutrophil bone marrow development, iii) identify novel surface markers for distinct neutrophil developmental stages and iv) provide evidence for neutrophil progenitor expansion in cancer.
2020-08-04 | GSE153263 | GEO
Project description:Severe congenital neutropenia (SCN) is a rare disorder characterized by a maturation arrest of myeloid progenitor cells in the bone marrow and severe reduction in the amount of circulating neutrophils. Loss-of-function mutations in the CSF3R (the gene encoding the granulocyte colony-stimulating factor (G-CSF) receptor) have been reported in a handful of cases. We describe two novel pedigrees with moderate neutropenia. G-CSFR immunostaining was greatly reduced on patient neutrophils. G-CSF did not prolong neutrophil survival or enhanced reactive oxygen species generation, and STAT-3 phosphorylation was absent, while neutrophils did respond to granulocyte-macrophage colony-stimulating factor (GM-CSF). Despite a lack of G-CSF signaling, morphology and cellular proteomics were normal. We suggest the major role of G-CSF is not in myeloid differentiation, but in generation of sufficient number of committed progenitor cells for neutrophil release and their survival during inflammation, which corresponds with G-CSFR expression in myeloid cell fractions from bone marrow of healthy individuals.
2020-09-25 | PXD018178 | Pride
Project description:Transcriptional profiling of clonal neutrophil progenitor populations. Conditionally immortalized CD45.1 naive paired granulocyte-monocyte progenitors (GMPs) and their mature neutrophil counterpart were profiled in an in vitro cell system. Clones demonstrated an overall similar transcriptional profile within the GMP or neutrophil states, however, individual clones had several differentially expressed genes (DEGs) between each other at both the progenitor and mature cell stages.
2022-09-27 | GSE188679 | GEO
Project description:Examination of open chromatin regions between clonal neutrophil progenitor populations. Conditionally immortalized CD45.1 naive paired granulocyte-monocyte progenitors (GMPs) and their mature neutrophil counterpart were profiled in an in vitro cell system. We identified 29,966 differentially accessible regions (DARs) between GMPs and neutrophils, from a total of 74,009 consensus peaks of chromatin accessibility. There is some correlation of open chromatin between GMP and mature neutrophil clones.
2022-09-27 | GSE188682 | GEO
Project description:Tumor-derived exosomes are emerging as mediators of tumorigenesis with a tissue-specific address and message. We explored the function of melanoma-derived exosomes in formation of primary tumors and metastatic progression in both murine models and patients. Whereas exosomes from highly metastatic melanoma cells increased the metastatic behavior of primary tumor cells by educating bone marrow (BM) progenitor cells via the MET receptor, exosomes from low metastatic melanoma cells did not alter the incidence of metastases. Melanoma-derived exosomes induced vascular leakiness at pre-metastatic sites, and reprogrammed BM progenitor cells towards a pro-vasculogenic phenotype (c-Kit+Tie2+MET+). Reducing MET expression in tumor-derived exosomes diminished the pro-metastatic behavior of BM cells. Importantly, MET expression was upregulated in circulating BM progenitor cells (CD45-CD117low and CD45-CD117lowTIE2+) isolated from stage III and stage IV melanoma patients. Rab1a, Rab5b, Rab7, and Rab27a were highly expressed in melanoma and Rab27a RNA interference decreased exosome production and/or soluble angiogenic factors in melanoma cells, thereby preventing mobilization of BM progenitor cells, tumor growth and metastasis. Finally, we identified a melanoma signature in exosomes isolated from metastatic melanoma patients, comprised of TYRP2, VLA-4, Hsp70, an Hsp90 isoform and MET oncoprotein, which together with Rab proteins, appear to represent exosome-specific proteins with prognostic potential, and may provide new therapeutic targets. Identification of molecular finger associated to exosome effects in metastatic organs Microarray analysis of genes differentially expressed in the lungs 24 and 48 hours after B16-F10 exosome tail vein injection compared to control.
2012-05-26 | E-GEOD-36584 | biostudies-arrayexpress