Transcriptional Heterogeneity and Lineage Commitment in Myeloid Progenitors

• Published in: Cell Vol. 163; no. 7; pp. 1663 - 1677
• Main Authors: Paul, Franziska, Arkin, Ya’ara, Giladi, Amir, Jaitin, Diego Adhemar, Kenigsberg, Ephraim, Keren-Shaul, Hadas, Winter, Deborah, Lara-Astiaso, David, Gury, Meital, Weiner, Assaf, David, Eyal, Cohen, Nadav, Lauridsen, Felicia Kathrine Bratt, Haas, Simon, Schlitzer, Andreas, Mildner, Alexander, Ginhoux, Florent, Jung, Steffen, Trumpp, Andreas, Porse, Bo Torben, Tanay, Amos, Amit, Ido
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 17.12.2015
• Subjects: Animals; Bone Marrow Transplantation; CCAAT-Enhancer-Binding Proteins - genetics; Gene Knockout Techniques; Hematopoiesis; High-Throughput Nucleotide Sequencing; Mice; Mice, Inbred C57BL; Myeloid Progenitor Cells - cytology; Myeloid Progenitor Cells - metabolism; Sequence Analysis, RNA; Single-Cell Analysis; Transcription Factors - metabolism; Transcriptome
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2015.11.013

Within the bone marrow, stem cells differentiate and give rise to diverse blood cell types and functions. Currently, hematopoietic progenitors are defined using surface markers combined with functional assays that are not directly linked with in vivo differentiation potential or gene regulatory mechanisms. Here, we comprehensively map myeloid progenitor subpopulations by transcriptional sorting of single cells from the bone marrow. We describe multiple progenitor subgroups, showing unexpected transcriptional priming toward seven differentiation fates but no progenitors with a mixed state. Transcriptional differentiation is correlated with combinations of known and previously undefined transcription factors, suggesting that the process is tightly regulated. Histone maps and knockout assays are consistent with early transcriptional priming, while traditional transplantation experiments suggest that in vivo priming may still allow for plasticity given strong perturbations. These data establish a reference model and general framework for studying hematopoiesis at single-cell resolution. [Display omitted] •Transcriptionally primed single-cell subpopulations in early myeloid progenitors•Transcription factors and epigenetic landscapes that regulate myeloid priming•Mixed lineage states are not observed but appear when regulation is perturbed•New reference model for studying hematopoiesis at single-cell resolution Single-cell transcriptomic analysis of bone marrow myeloid progenitor populations reveals early transcriptional priming toward seven different fates and absence of progenitors of mixed lineages, challenging the current models of hematopoiesis based on progressive loss of differentiation potential.