A single-cell hematopoietic landscape resolves 8 lineage trajectories and defects in Kit mutant mice.
Joakim S Dahlin, Fiona K Hamey, Blanca Pijuan-Sala, Mairi Shepherd, Winnie W Y Lau, Sonia Nestorowa, Caleb Weinreb, Samuel Wolock, Rebecca Hannah, Evangelia Diamanti, David G Kent, Berthold Göttgens, Nicola K Wilson
Author Information
Joakim S Dahlin: Department of Haematology, University of Cambridge, Cambridge Institute for Medical Research and Wellcome-Medical Research Council Cambridge Stem Cell Institute, Cambridge, United Kingdom. ORCID
Fiona K Hamey: Department of Haematology, University of Cambridge, Cambridge Institute for Medical Research and Wellcome-Medical Research Council Cambridge Stem Cell Institute, Cambridge, United Kingdom. ORCID
Blanca Pijuan-Sala: Department of Haematology, University of Cambridge, Cambridge Institute for Medical Research and Wellcome-Medical Research Council Cambridge Stem Cell Institute, Cambridge, United Kingdom.
Mairi Shepherd: Department of Haematology, University of Cambridge, Wellcome-Medical Research Council Cambridge Stem Cell Institute, Cambridge, United Kingdom; and.
Winnie W Y Lau: Department of Haematology, University of Cambridge, Cambridge Institute for Medical Research and Wellcome-Medical Research Council Cambridge Stem Cell Institute, Cambridge, United Kingdom.
Sonia Nestorowa: Department of Haematology, University of Cambridge, Cambridge Institute for Medical Research and Wellcome-Medical Research Council Cambridge Stem Cell Institute, Cambridge, United Kingdom.
Caleb Weinreb: Department of Systems Biology, Harvard Medical School, Boston, MA.
Samuel Wolock: Department of Systems Biology, Harvard Medical School, Boston, MA.
Rebecca Hannah: Department of Haematology, University of Cambridge, Cambridge Institute for Medical Research and Wellcome-Medical Research Council Cambridge Stem Cell Institute, Cambridge, United Kingdom.
Evangelia Diamanti: Department of Haematology, University of Cambridge, Cambridge Institute for Medical Research and Wellcome-Medical Research Council Cambridge Stem Cell Institute, Cambridge, United Kingdom.
David G Kent: Department of Haematology, University of Cambridge, Wellcome-Medical Research Council Cambridge Stem Cell Institute, Cambridge, United Kingdom; and.
Berthold Göttgens: Department of Haematology, University of Cambridge, Cambridge Institute for Medical Research and Wellcome-Medical Research Council Cambridge Stem Cell Institute, Cambridge, United Kingdom.
Nicola K Wilson: Department of Haematology, University of Cambridge, Cambridge Institute for Medical Research and Wellcome-Medical Research Council Cambridge Stem Cell Institute, Cambridge, United Kingdom.
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.
