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• W2898830367 abstract "Abstract Introduction: Human hemopoiesis produces 10 billion new, terminally mature blood cells daily; a production that is also rapidly responsive to external stimuli. Dysregulation of this complex process can lead to hemopoietic and immune deficiencies and blood cancers. In humans, the hemopoietic progenitor hierarchy producing lymphoid and myeloid lineages is unclear. Multiple progenitor populations give rise to lymphoid and myeloid cells but they remain incompletely characterized at the immunophenotypic, transcriptional and functional level. Here, we aim to understand the clonal functional output and transcriptional programs of primary human lympho-myeloid progenitor populations - the lymphoid-primed multipotent progenitor (LMPP) (Goardon et al., Cancer Cell, 2011), the multi-lymphoid progenitor (MLP) (Doulatov et al., Nature Immunology, 2010) and the granulocyte-macrophage progenitor (GMP). Methods: We devised a FACS strategy to prospectively purify eight human hemopoietic stem and progenitor cell populations. We functionally compared the LMPP, MLP and GMP in vitro by quantitative CFU assays, three different single cell liquid cultures or limit dilution analysis and in vivo by transplantation into a humanized ossicle mouse model (Reinisch et al., Nature Medicine, 2016). We performed population and single cell RNA sequencing and Fluidigm qRT-PCR to understand the relationship between the functional and transcriptional heterogeneity within human lympho-myeloid progenitor populations. Results: Our study comprehensively characterized the LMPP, MLP and GMP lympho-myeloid progenitor populations. Both LMPP and MLP are very rare within the mononuclear fraction (1 in 104 and 1 in 105 cells in CB and BM, respectively). We cultured 4357 single LMPP, GMP and MLP cells (isolated from 25 cord blood units and equivalent to ~1010 mononuclear cells) under three different culture conditions, one of which is described for the first time. We observed marked functional heterogeneity in the three lympho-myeloid progenitor populations. Focusing on the wells that gave single cell-initiated cultures, the majority of cells from LMPP, MLP and GMP gave uni-lineage output (60-90%). Bi-lineage output was less common (up to 35%), while multi-lineage output was the least frequent and only observed from LMPP and GMP cells (up to 15%). In vivo transplantation using the humanized ossicle mouse model increased the engraftment of lympho-myeloid progenitors 10-fold compared to previous reports. In vivo, the LMPP and GMP gave robust engraftment but the MLP substantially less engraftment. The LMPP gave rise to both myeloid and B cell engraftment, the GMP to myeloid engraftment and the MLP mainly to B cell output. Population RNA sequencing revealed distinct transcriptional signatures of these populations: MLP signature was enriched for lymphoid-affiliated genes, GMP for myeloid-affiliated genes and LMPP had a hybrid lympho-myeloid signature. Single cell RNA sequencing of 320 LMPP, MLP and GMP cells showed that the 3 progenitor populations form a transcriptional continuum. Linking the single cell gene expression to FACS indexing allowed exclusive purification of lymphoid- and myeloid-only progenitors from the current LMPP and GMP populations. Conclusions: These data change our understanding of human hematopoiesis and offer a radically new model of human lympho-myeloid progenitor specification. This model may have important implications for human immune deficiencies and hemopoietic malignancies. BS and DK contributed equally to this work. FH and AR contributed equally to this work. Disclosures Quek: Celgene Corporation: Research Funding. Vyas: Jazz Pharmaceuticals: Speakers Bureau; Celgene Corporation: Speakers Bureau." @default.
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• W2898830367 date "2017-12-07" @default.
• W2898830367 modified "2023-10-02" @default.
• W2898830367 title "A Novel Model of Human Hemopoiesis Based on Single Cell Functional and Transcriptional Analysis of Lympho-Myeloid Progenitors" @default.
• W2898830367 doi "https://doi.org/10.1182/blood.v130.suppl_1.2413.2413" @default.
• W2898830367 hasPublicationYear "2017" @default.
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