Human haematopoietic stem cell lineage commitment is a continuous process
Open accessAbstract
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.
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Key hematopoietic TFs are expressed in smooth, overlapping gradients throughout stem and progenitor populations, whereas their target genes display cell-state-specific expression patterns.
“single-cell transcriptomics1,2,3 and imaging-based4 studies have demonstrated that key TFs are expressed in smooth, overlapping gradients throughout the stem and progenitor populations (Figure 1A, top row); by contrast, the target genes regulated by these factors display cell-state-specific expression patterns (Figure 1A, bottom row).”
From Design principles of cell-state-specific enhancers in hematopoiesis (2025) · cites this paper as [2]
The Results sections “Early haematopoiesis is a continuous process” and “Molecular processes underlying HSC commitment” describe gradual differences among primitive cells and non-exclusive expression of early lineage-priming modules. They do not establish smooth, overlapping gradients of key transcription factors throughout both stem and progenitor populations, or the claimed contrast between those factors and their target genes; the paper also describes lineage-specific transcription-factor modules in later progenitors. Page numbers were not available in our copy. (LLM, conf=0.82)
Experimental — accuracy not yet measuredProgenitors with different fate potentials did not split into discrete cell states but formed a structured continuum, matching recent scSeq studies.
“Consistent with recent scSeq studies (19), progenitors with different fate potentials did not partition into discrete cell states, but instead formed a structured continuum.”
From Lineage tracing on transcriptional landscapes links state to fate during differentiation (2020) · cites this paper as [19]
NR4A1/2 have been demonstrated to maintain HSC quiescence.
“NR4A1/2 have been demonstrated to maintain HSC quiescence 32-34 .”
From Type 1 interferon perturbates clonal competition by reshaping human blood development (2026) · cites this paper as [33]
The Results section ('Molecular processes underlying HSC commitment'; page not provided) associates the least-primed HSC state with cell-cycle quiescence, but does not say that NR4A1 or NR4A2 maintains it. Searches for 'NR4A1/2' and for those factors with HSC quiescence found no passage addressing their role. (LLM, conf=0.72)
Experimental — accuracy not yet measuredIn the continuum model, differentiation from HSCs to progenitors to mature functional cells occurs constantly and without distinct punctuated phenotypic changes.
“In this continuum model, the process of differentiation from HSCs to progenitors to mature functional cells is envisioned as occurring constantly and without the distinct punctuated phenotypic changes that exist within the classic model of hematopoiesis (Laurenti and Göttgens, 2018; Velten et al., 2017).”
From Unraveling Hematopoiesis through the Lens of Genomics (2020) · cites this paper as Velten et al., 2017
There is support for cells expressing distinct modules of transcriptional programs that cooperate to subtly and continuously prime cells to differentiate along target lineages.
“It is still unclear how continuous lineage decisions could be made, but there is support for cells expressing distinct modules of transcriptional programs that cooperate to subtly and continuously prime cells to differentiate along target lineages (Giladi et al., 2018; Velten et al., 2017).”
From Unraveling Hematopoiesis through the Lens of Genomics (2020) · cites this paper as Velten et al., 2017
In the absence of fate tracking, all inferred biases in native hematopoiesis are speculative.
“Finally, while single-cell genomic approaches have produced compelling evidence that observed cellular heterogeneity reflects downstream lineage decisions (Herring et al., 2018; La Manno et al., 2018; Rodriguez-Fraticelli et al., 2018), in the absence of fate tracking, all inferred biases in native hematopoiesis are speculative (Pina et al., 2012; Velten et al., 2017).”
From Unraveling Hematopoiesis through the Lens of Genomics (2020) · cites this paper as Velten et al., 2017
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“Consistent with recent scSeq studies (19), progenitors with different fate potentials did not partition into discrete cell states, but instead formed a structured continuum.”
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- Authors
- Velten, L., Haas, S. F., Raffel, S., Blaszkiewicz, S., Islam, S., Hennig, B. P., Hirche, C., Lutz, C., Buss, E. C., Nowak, D., Boch, T., Hofmann, W.-K., Ho, A. D., Huber, W., Trumpp, A., Essers, M. A. G., & Steinmetz, L. M.
- Affiliations
- European Molecular Biology Laboratory (DE)
- German Cancer Research Center (DE)
- Stanford Medicine (US)
- Heidelberg University (DE)
- Corresponding author
- Trumpp, Andreas
- Essers, Marieke A. G.
- Steinmetz, Lars M.
- ORCID
- Venue
- Nature Cell Biology
- Published
- 2017-03-20
- Volume
- 19
- Issue
- 4
- Pages
- 271-281
- ISSN
- 1465-7392 (ISSN-L)
- 1476-4679
- PMC
- PMC5496982
- OpenAlex
- W2602848567
- Cited by
- 925
- References
- 54
- Citations by year
- 2026: 50 · 2025: 75 · 2024: 85 · 2023: 104 · 2022: 115 · 2021: 118 · 2020: 142 · 2019: 110 · 2018: 94 · 2017: 32
- FWCI
- 81.98
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature Cell Biology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- MDC Repository (Max-Delbrueck-Center for Molecular Medicine) (submittedVersion)
- Funders
- National Human Genome Research Institute (P01HG000205)
- Topics
- Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Single-cell and spatial transcriptomics
- Health Sciences › Medicine › Genetics › Mesenchymal stem cell research
- Keywords
- hematopoietic stem cells, lineage commitment, hematopoiesis, hematopoietic progenitor cells, stemness, lineage priming, gene modules, single-cell transcriptomics, hematologic malignancies
- MeSH terms
- Adult, Animals, Female, Hematopoiesis, Hematopoietic Stem Cells, Humans, Male, Models, Biological, Antigens, CD, Cell Lineage, Multipotent Stem Cells, Cell Proliferation, Mice, Gene Regulatory Networks, Transcriptome
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