Single-cell characterization of haematopoietic progenitors and their trajectories in homeostasis and perturbed haematopoiesis

Abstract

The dynamics of haematopoietic stem cell differentiation and the hierarchy of oligopotent stem cells in the bone marrow remain controversial. Here we dissect haematopoietic progenitor populations at single cell resolution, deriving an unbiased reference model of transcriptional states in normal and perturbed murine bone marrow. We define the signature of the naive haematopoietic stem cell and find a continuum of core progenitor states. Core cell populations mix transcription of pre-myeloid and pre-lymphoid programs, but do not mix erythroid or megakaryocyte programs with other fates. CRISP-seq perturbation analysis confirms our models and reveals that Cebpa regulates entry into all myeloid fates, while Irf8 and PU.1 deficiency block later differentiation towards monocyte or granulocyte fates. Our transcriptional map defines a reference network model for blood progenitors and their differentiation trajectories during normal and perturbed haematopoiesis.

Erythropoietin directly remodels the clonal composition of murine hematopoietic multipotent progenitor cells

“…In early studies, high EPO levels were associated with increased HSC proliferation 15,21 . More recently, upregulation of cell cycle-related genes in HSCs following an increase of EPO levels in vivo corroborated these findings 17,18,20 . In addition, an increased EPO level was found to impact expression of immune response genes 18 or bone homeostasis-associated genes 13 in HSCs.…”

“…EPO has been shown to also target hematopoietic niche cells (osteoblasts and osteocytes 8,9 , endothelial cells 10,9 , adipocytes 11,12 , mesenchymal stem cells 13,14 ). In the hematopoietic hierarchy, EPO has also been suggested to act on hematopoietic stem and progenitor cells 15,13,16,17,18,19,20,21 , but several aspects remain debated.…”

Defining the emergence of myeloid-derived suppressor cells in breast cancer using single-cell transcriptomics

“…Interrogating our observed cell states using pseudotemporal ordering and comparing these to recent work that defined the signatures of various haematopoietic stem and progenitor cell states in single-cell resolution 17 allowed us to reconstruct that MDSCs form an aberrant trajectory from neutrophil progenitor cells that occurs at the cost of normal differentiation into mature neutrophil granulocytes, which are less abundant in tumor-bearing mice (Fig. 3A).…”

“…For cell type subset analyses (Monocytes and Neutrophils), clusters with high expression of cell type markers (Csf1r and Ly6g, respectively) were subset out and standard Seurat workflow was applied on each. In the case of the neutrophil-specific analysis, a population of cells that grouped together and expressed a set of markers associated with neutrophil progenitors 17 was manually labeled and treated as a distinct cluster for analysis. Starting with all cells from the WT and PyMT combined analysis, neutrophils were specifically subset out.…”

Fate mapping via Ms4a3 expression history traces monocyte-derived cells

“…Here we aimed to develop a new fate-mapping mouse model specific for monocyte progenitors that could precisely measure the contribution of monocytes to RTM populations under any condition and discern monocytes from DCs. The earliest monopotent BM progenitors giving rise to monocytes are common monocyte progenitors (cMoPs) (Hettinger et al, 2013), although commitment to monocytes occurs earlier as shown by single-cell mRNA sequencing (scRNA-seq) (Giladi et al, 2018;Paul et al, 2015). cMoPs are proposed to arise from the hierarchical model of common myeloid progenitor (CMP) à granulocyte-monocyte progenitor (GMP) à monocytedendritic cell progenitors (MDP) à common monocyte progenitor (cMoP) (Guilliams et al, 2018;Terry and Miller, 2014).…”