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Uncovering two neutrophil-committed progenitors that immediately precede the promyelocytes during human neutropoiesis

ABSTRACT: Technological advances have greatly improved our knowledge of myelopoiesis, for instance with the discovery of granulocyte-monocyte-DC progenitors (GMDPs), monocyte-DC progenitors (MDPs), common dendritic progenitors (CDPs) and common monocyte progenitors (cMoPs) based on sophisticated flow cytometry approaches. Concomitantly, little progress has been made to characterize the very early phases of human neutropoiesis, despite the recently reported eNePs, PM w/o eNePs, ProNeus, preNeus, all of them being, however, CD66b+neutrophil progenitors. More recently, we identified four SSCloLin-CD66b-CD45dimCD34+/CD34dim/-CD64dimCD115-cells as the earliest precursors specifically committed to the neutrophil lineage present in human bone marrow (BM), which we called neutrophil-committed progenitors (NCPs), namely from NCP1s to NCP4s. In this study, we report the isolation and characterization of two new SSChiCD66b-CD64dimCD115-NCPs that, by phenotypic, flow cytometric SSC, transcriptomic, maturation and immunohistochemistry properties/features, stand after NCP4s but precede the CD66b+Promyelocytes (PMs) during the neutropoiesis cascade. These cells, similarly to SSCloCD45RA+NCP2s/NCP3s and SSCloCD45RA-NCP1s/NCP4s, exhibit phenotypic differences in CD45RA expression levels and, therefore, were named as SSChiCD45RA+NCP5s and SSChiCD45RA-NCP6s. In addition, NCP5s result more immature than NCP6s, as determined by both their cell differentiation and proliferative potential, and by their transcriptomic and phenotypical features. Finally, by examining whether NCPs and all other CD66b+neutrophil precursors are altered in representative hematological malignancies, we found that, in patients with chronic-phase chronic myeloid leukemia (CP-CML), but not with systemic mastocytosis (SM), there is an increased frequency of NCP4s and all downstream neutrophil progenitors, particularly, the CD45RA-cells, like NCP6s, suggesting their involvement in CML pathogenesis. Altogether, our data advance our knowledge of human neutropoiesis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE274002 | GEO | 2025/03/05

REPOSITORIES: GEO

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Project description:The advent of recent cutting-edge technologies has allowed the discovery and characterization of novel hematopoietic progenitors, including SSCloCD66b+CD15+CD11b-CD49dhiproNeu1s and SSChiCD66b+CD15+CD11b-CD49dintproNeus2s, CD66b+CD15+CD11b+CD49d+CD101-preNeus and Lin-CD66b+CD117+CD71+eNePs along human neutropoiesis process. In this research field, we recently identified CD66b-CD38+CD64dimCD115-, CD34+ and CD34dim/-cells exclusively committed to the neutrophil lineage [which we renamed as CD34+ and CD34dim/- neutrophil-committed progenitors (NCPs)], representing the earliest neutrophil precursors identifiable and sorted by flow cytometry. Moreover, based on their differential CD34 and CD45RA expression, we could identify four populations of NCPs, namely: CD34+CD45RA-/NCP1s, CD34+CD45RA+/NCP2s, CD34dim/-CD45RA+/NCP3s and CD34dim/-CD45RA-/NCP4s. This said, a very recent study by Ikeda and coworkers (PMID: 36862552) reported that neutrophil precursors termed either neutrophil progenitors (NePs) or “early neutrophil-committed progenitors” would generate immunosuppressive neutrophil-like CXCR1+CD14+CD16-monocytes. Hence, presuming that NePs/alias “early neutrophil-committed progenitors” correspond to NCPs, the selective neutrophil-commitment that we attributed to NCPs is contradicted by Ikeda and coworkers’ paper. In this study, by performing a more analytical reevaluation at the phenotypic and molecular levels of the cells generated by NCP2s and NCP4s (selected as representatives of NCPs), we categorically exclude that NCPs generate neutrophil-like CXCR1+CD14+CD16-monocytes. Rather, we provide substantial evidence indicating that the cells generated by NePs/alias “early neutrophil-committed progenitors” are neutrophilic cells at different stage of maturation, displaying moderate levels of CD14, instead of neutrophil-like CXCR1+CD14+CD16-monocytes as pointed by Ikeda and coworkers. Hence, the conclusion that NePs/alias “early neutrophil-committed progenitors” aberrantly differentiate into neutrophil-like monocytes derives, in our opinion, from data misinterpretation

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.

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Uncovering two neutrophil-committed progenitors that immediately precede the promyelocytes during human neutropoiesis

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