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Coexpression of CD71 and CD117 Identifies an Early Unipotent Neutrophil Progenitor Population in Human Bone Marrow.

ABSTRACT: Neutrophils are the most abundant peripheral immune cells and thus, are continually replenished by bone marrow-derived progenitors. Still, how newly identified neutrophil subsets fit into the bone marrow neutrophil lineage remains unclear. Here, we use mass cytometry to show that two recently defined human neutrophil progenitor populations contain a homogeneous progenitor subset we term "early neutrophil progenitors" (eNePs) (Lin^-CD66b⁺CD117⁺CD71⁺). Surface marker- and RNA-expression analyses, together with in vitro colony formation and in vivo adoptive humanized mouse transfers, indicate that eNePs are the earliest human neutrophil progenitors. Furthermore, we identified CD71 as a marker associated with the earliest neutrophil developmental stages. Expression of CD71 marks proliferating neutrophils, which were expanded in the blood of melanoma patients and detectable in blood and tumors from lung cancer patients. In summary, we establish CD117⁺CD71⁺ eNeP as the inceptive human neutrophil progenitor and propose a refined model of the neutrophil developmental lineage in bone marrow.

SUBMITTER: Dinh HQ

PROVIDER: S-EPMC7942809 | biostudies-literature |

REPOSITORIES: biostudies-literature

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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.

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Coexpression of CD71 and CD117 Identifies an Early Unipotent Neutrophil Progenitor Population in Human Bone Marrow.

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