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An immunophenotype coupled transcriptomic atlas of human hematopoietic progenitors

ABSTRACT: Understanding the cellular heterogeneity and lineage potential of human bone marrow hematopoietic progenitors is required to understand normal differentiation and the mechanisms of hematological disease. Central to this objective are protocols that enable the delineation, isolation and functional characterization or known and novel cell populations, which are traditionally empowered by flow cytometry. Recognizing the need for tackling cellular heterogeneity, we have designed a use case for compiling next-generation processing methods via existing and highly curated single-cell interrogation technologies. Multi-omics approaches, such as Cellular Indexing of Transcriptomes and Epitopes by Sequencing (CITE-seq), enable concurrent transcriptomic and immunophenotyping at a single-cell level but necessitate precision antibody titration mixes that can be directly integrated with parallel flow cytometry strategies. To bridge this gap, we performed a molecular titration of 266 antibodies using primary human bone marrow cells spanning race and sex to approximate diversity. Through machine learning and user curation, we created an optimized titrated bone marrow CITE-seq panel of 132 antibodies. Multimodal integration of these data using a game-theory driven approach, improved our ability to resolve new stable stem, progenitor, and transitional cell populations, readily defined by unique RNA and ADT markers. Leveraging complexity-matching high-dimensional flow cytometry (pyInfinityFlow), we consolidated the findings from CITE-seq and subsequently developed novel isolation strategies for maturing granulocytes, late-stage erythroid progenitors and improved purification of megakaryocyte/erythrocyte progenitors (MEP). Finally, we integrated CITE-seq with flow cytometry data from matching donors, successfully identified 37 cell surface markers consistently expressed across donors and technologies. The compiled bone marrow cell atlas serves as an advanced digital analytical resource for progenitor analyses in health and disease.

ORGANISM(S): Homo sapiens

PROVIDER: GSE245108 | GEO | 2024/01/26

REPOSITORIES: GEO

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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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An immunophenotype coupled transcriptomic atlas of human hematopoietic progenitors

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