Human haematopoietic stem cell lineage commitment is a continuous process.
Blood formation is believed to occur through stepwise progression of haematopoietic stem cells (HSCs) following a tree-like hierarchy of oligo-, bi- and unipotent progenitors. However, this model is based on the analysis of predefined flow-sorted cell populations. Here we integrated flow cytometric, transcriptomic and functional data at single-cell resolution to quantitatively map early differentiation of human HSCs towards lineage commitment. During homeostasis, individual HSCs gradually acquire lineage biases along multiple directions without passing through discrete hierarchically organized progenitor populations. Instead, unilineage-restricted cells emerge directly from a 'continuum of low-primed undifferentiated haematopoietic stem and progenitor cells' (CLOUD-HSPCs). Distinct gene expression modules operate in a combinatorial manner to control stemness, early lineage priming and the subsequent progression into all major branches of haematopoiesis. These data reveal a continuous landscape of human steady-state haematopoiesis downstream of HSCs and provide a basis for the understanding of haematopoietic malignancies.
European Molecular Biology Laboratory (EMBL), Genome Biology Unit, 69117 Heidelberg, Germany.
Lars
L
Velten
Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), 69120 Heidelberg, Germany.|Division of Stem Cells and Cancer, Haematopoietic Stem Cells and Stress Group, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.|Division of Stem Cells and Cancer and DKFZ-ZMBH Alliance, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
Simon F
SF
Haas
Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), 69120 Heidelberg, Germany.|Division of Stem Cells and Cancer and DKFZ-ZMBH Alliance, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.|Department of Internal Medicine V, University of Heidelberg, 69120 Heidelberg, Germany.
Simon
S
Raffel
Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), 69120 Heidelberg, Germany.|Division of Stem Cells and Cancer, Haematopoietic Stem Cells and Stress Group, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
Sandra
S
Blaszkiewicz
Department of Genetics, Stanford University School of Medicine, Stanford, California 94305, USA.
Saiful
S
Islam
European Molecular Biology Laboratory (EMBL), Genome Biology Unit, 69117 Heidelberg, Germany.
Bianca P
BP
Hennig
Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), 69120 Heidelberg, Germany.|Division of Stem Cells and Cancer, Haematopoietic Stem Cells and Stress Group, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
Christoph
C
Hirche
Department of Internal Medicine V, University of Heidelberg, 69120 Heidelberg, Germany.
Christoph
C
Lutz
Department of Internal Medicine V, University of Heidelberg, 69120 Heidelberg, Germany.
Eike C
EC
Buss
Department of Hematology and Oncology, Medical Faculty Mannheim, University of Heidelberg, 68167 Mannheim, Germany.
Daniel
D
Nowak
Department of Hematology and Oncology, Medical Faculty Mannheim, University of Heidelberg, 68167 Mannheim, Germany.
Tobias
T
Boch
Department of Hematology and Oncology, Medical Faculty Mannheim, University of Heidelberg, 68167 Mannheim, Germany.
Wolf-Karsten
WK
Hofmann
Department of Internal Medicine V, University of Heidelberg, 69120 Heidelberg, Germany.
Anthony D
AD
Ho
European Molecular Biology Laboratory (EMBL), Genome Biology Unit, 69117 Heidelberg, Germany.
Wolfgang
0000-0002-0474-2218
W
Huber
Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), 69120 Heidelberg, Germany.|Division of Stem Cells and Cancer and DKFZ-ZMBH Alliance, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.|German Cancer Consortium (DKTK), 69120 Heidelberg, Germany.
Andreas
A
Trumpp
Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), 69120 Heidelberg, Germany.|Division of Stem Cells and Cancer, Haematopoietic Stem Cells and Stress Group, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
Marieke A G
MA
Essers
European Molecular Biology Laboratory (EMBL), Genome Biology Unit, 69117 Heidelberg, Germany.|Department of Genetics, Stanford University School of Medicine, Stanford, California 94305, USA.|Stanford Genome Technology Center, Palo Alto, California 94304, USA.
Lars M
LM
Steinmetz
D000328:Adult; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D019070:Cell Lineage / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D005260:Female; D053263:Gene Regulatory Networks; D006410:Hematopoiesis / Q000235:genetics; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008954:Models, Biological; D039902:Multipotent Stem Cells / Q000166:cytology / Q000378:metabolism; D059467:Transcriptome / Q000235:genetics
D015703:Antigens, CD