Department of Molecular, Cell and Cancer Biology; Division of Infectious Diseases and Immunology, Department of Medicine; UMass Metabolic Network
Cell Biology | Cells | Developmental Biology | Hemic and Immune Systems | Systems Biology
Red cell formation begins with the hematopoietic stem cell, but the manner by which it gives rise to erythroid progenitors, and their subsequent developmental path, remain unclear. Here we combined single-cell transcriptomics of murine hematopoietic tissues with fate potential assays to infer a continuous yet hierarchical structure for the hematopoietic network. We define the erythroid differentiation trajectory as it emerges from multipotency and diverges from 6 other blood lineages. With the aid of a new flow-cytometric sorting strategy, we validated predicted cell fate potentials at the single cell level, revealing a coupling between erythroid and basophil/mast cell fates. We uncovered novel growth factor receptor regulators of the erythroid trajectory, including the proinflammatory IL- 17RA, found to be a strong erythroid stimulator; and identified a global hematopoietic response to stress erythropoiesis. We further identified transcriptional and high-purity FACS gates for the complete isolation of all classically-defined erythroid burst-forming (BFU-e) and colony-forming progenitors (CFU-e), finding that they express a dedicated transcriptional program, distinct from that of terminally-differentiating erythroblasts. Intriguingly, profound remodeling of the cell cycle is intimately entwined with CFU-e developmental progression and with a sharp transcriptional switch that extinguishes the CFU-e stage and activates terminal differentiation. Underlying these results, our work showcases the utility of theoretic approaches linking transcriptomic data to predictive fate models, providing key insights into lineage development in vivo.
hematopoietic stem cell, erythroid progenitors, single-cell transcriptomics, IL- 17RA, systems biology
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The copyright holder for this preprint (which was not peer-reviewed) is the author/funder. It is made available under a CC-BY-NC 4.0 International license.
DOI of Published Version
bioRxiv 261941; doi: https://doi.org/10.1101/261941. Link to preprint on bioRxiv service.
Tusi, Betsabeh K.; Wolock, Samuel L.; Weinreb, Caleb; Hwang, Yung; Hidalgo, Daniel; Zilionis, Rapolas; Waisman, Ari; Huh, Jun R.; Klein, Allon M.; and Socolovsky, Merav, "Emergence of the erythroid lineage from multipotent hematopoiesis" (2018). University of Massachusetts Medical School Faculty Publications. 1507.
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This work is licensed under a Creative Commons Attribution-Noncommercial 4.0 License