A single-cell hematopoietic landscape resolves 8 lineage trajectories and defects in Kit mutant mice

Abstract

Hematopoietic stem and progenitor cells (HSPCs) maintain the adult blood system, and their dysregulation causes a multitude of diseases. However, the differentiation journeys toward specific hematopoietic lineages remain ill defined, and system-wide disease interpretation remains challenging. Here, we have profiled 44 802 mouse bone marrow HSPCs using single-cell RNA sequencing to provide a comprehensive transcriptional landscape with entry points to 8 different blood lineages (lymphoid, megakaryocyte, erythroid, neutrophil, monocyte, eosinophil, mast cell, and basophil progenitors). We identified a common basophil/mast cell bone marrow progenitor and characterized its molecular profile at the single-cell level. Transcriptional profiling of 13 815 HSPCs from the c-Kit mutant (W/W) mouse model revealed the absence of a distinct mast cell lineage entry point, together with global shifts in cell type abundance. Proliferative defects were accompanied by reduced expression. Potential compensatory processes included upregulation of the integrated stress response pathway and downregulation of proapoptotic gene expression in erythroid progenitors, thus providing a template of how large-scale single-cell transcriptomic studies can bridge between molecular phenotypes and quantitative population changes.

Frontline Science: Mast cells regulate neutrophil homeostasis by influencing macrophage clearance activity

“…Indeed, due to the early expression of cKit in hematopoietic stem cells, its mutation can affect not only SCF‐dependent MC differentiation and maturation but also other hematopoietic lineages. In a recent study, a single‐cell transcriptional profile of bone marrow‐derived hematopoietic stem cells and progenitor cells from a Kit‐mutant W41/W41 mouse (characterized by a missense mutation in the kinase domain of the Kit coding sequence that causes a partial loss of protein function) revealed that impaired cKit signaling exerts global effects on hematopoietic lineages with reduced MC and basophil progenitor cluster and a concomitant increase of neutrophil progenitors …”

Kit ligand has a critical role in mouse yolk sac and aorta–gonad–mesonephros hematopoiesis

“…Cdkn1a (p21) displayed a similar trend ( Fig 8E). FL erythroid precursors showed downregulation of Stat5a, known to promote erythroid cell proliferation and differentiation downstream of Kit [54], and Myc, which was described to mediate cell cycle progression in erythroblasts [55] and was recently shown to be downregulated in Kit W 41 mutants underlying their proliferative defects [56] ( Fig 8E). In addition, we observed an upregulation in the anti-apoptotic gene Bcl2l1 (Bcl-xL) in FL populations (Appendix Fig S3).…”

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

“…1,706 cells from control and 1,595 cells from the EPO group passed our quality control and were mapped to a published dataset to perform supervised cell type annotation. We generated a reference map of 44,802 ckit + cells from 55 and used published signatures 56,19,57 to annotate this map for ckit + cells, LSK, MPP4, lymphoid, erythrocytes, megakaryocyte and myeloid progenitors ( Fig. 4a and Supplementary Fig.…”