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Identification of a CD117+ CD71+ early unipotent neutrophil progenitor population in human bone marrow

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE153263 | GEO | 2020/08/04

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:An expansion of neutrophils often marks cancer. To date, neutrophils are assumed to be a relatively homogenous population, but recent studies describe both pro- and anti-tumor functions in neutrophils. This suggests there is more heterogeneity in neutrophils than previously appreciated. To better understand and target neutrophil functions in cancer, we must dissect neutrophil heterogeneity and how it changes from health to disease. To this end, we employed single-cell transcriptome technology to profile immature neutrophils from bone marrow of healthy individuals. Intriguingly, we identified a new neutrophil subset that expresses several B cell markers, including CD79a/b, components of the B cell receptors and PAX5, a lineage-specific transcriptional factor. We termed this population the BNeut. Using flow cytometry, we found that BNeuts are confined to the bone marrow of healthy individuals but expand into the blood of melanoma patients at an early stage, suggesting BNeuts might be a biomarker for disease. Additionally, we find BNeuts in the mouse models of different cancer types, including breast and lung carcinoma. The BNeut appears and functions more similar to a neutrophil than a B cell. BNeuts possess a neutrophil-like transcriptional profile, large cytoplasm with segmented nucleus, and produce ROS and NETs. Using imaging, we show that the BNeuts are single cells co-expressing both CD66b and CD79b, and lack the B cell surface marker CD19. To understand why neutrophils might use a B cell program, we explored different B cell functions including antigen presentation, a function that is usually absent from neutrophils. We show BNeuts are excellent at phagocytosis, including uptake of tumor cells. Further, BNeuts have increased expression of antigen presentation-related genes compared to other neutrophils and can modulate CD4+ T cell responses. Together, we have identified a novel neutrophil subset expressing B cell markers that is preferentially expanded in the blood of melanoma patients and poised to control T cell responses during disease.

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Identification of a CD117+​ ​CD71+​ ​ early ​unipotent​ neutrophil progenitor population in human bone marrow

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Identification of a CD117+ CD71+ early unipotent neutrophil progenitor population in human bone marrow