A latent subset of human hematopoietic stem cells resists regenerative stress to preserve stemness
Open accessAbstract
Continuous supply of immune cells throughout life relies on the delicate balance in the hematopoietic stem cell (HSC) pool between long-term maintenance and meeting the demands of both normal blood production and unexpected stress conditions. Here we identified distinct subsets of human long-term (LT)-HSCs that responded differently to regeneration-mediated stress: an immune checkpoint ligand CD112 lo subset that exhibited a transient engraftment restraint (termed latency) before contributing to hematopoietic reconstitution and a primed CD112 hi subset that responded rapidly. This functional heterogeneity and CD112 expression are regulated by INKA1 through direct interaction with PAK4 and SIRT1, inducing epigenetic changes and defining an alternative state of LT-HSC quiescence that serves to preserve self-renewal and regenerative capacity upon regeneration-mediated stress. Collectively, our data uncovered the molecular intricacies underlying HSC heterogeneity and self-renewal regulation and point to latency as an orchestrated physiological response that balances blood cell demands with preserving a stem cell reservoir.
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TGFB1 encodes the pro-fibrotic cytokine TGFb, established as one of the main inducers of myelofibrosis in patients with fibrotic-phase MPN.
“We also observed a downregulation of TGFB1 ( Supplementary Fig. 4b ), that encodes the pro-fibrotic cytokine TGFb established as one of the main inducers of myelofibrosis in patients with fibrotic-phase of MPN 50,51 .”
From Type 1 interferon perturbates clonal competition by reshaping human blood development (2026) · cites this paper as [51]
The cited paper’s PAK4-inhibition section (pp. 20–21) discusses hematopoietic stem-cell responses to treatment, not TGFB1 or fibrosis. Searches of our copy for TGFB1, TGF-beta, and myelofibrosis found no passage addressing the claimed role of TGF-beta in fibrotic-phase MPN. (LLM, conf=0.75)
Experimental — accuracy not yet measuredMPN megakaryocytes exhibit higher expression of TGFB1.
“We and others have shown that MPN megakaryocytes indeed exhibit higher expression of TGFB1 20,50,51 , and thus downregulation of TGFB1 by IFNa may be a key mechanism of improvement in fibrosis frequently observed in patients treated with IFNa.”
From Type 1 interferon perturbates clonal competition by reshaping human blood development (2026) · cites this paper as [51]
The Extended Data Fig. 6 description (p. 5) mentions megakaryocytic cells only as an output of stem-cell differentiation assays; it does not address MPN megakaryocytes or TGFB1 expression. Searches for “MPN megakaryocytes TGFB1,” “transforming growth factor beta 1,” and “TGFB1” found no passage supporting the attributed comparison. (LLM, conf=0.75)
Experimental — accuracy not yet measuredDownregulation of TGFB1 by IFNa may be a key mechanism of improvement in fibrosis frequently observed in patients treated with IFNa.
“We and others have shown that MPN megakaryocytes indeed exhibit higher expression of TGFB1 20,50,51 , and thus downregulation of TGFB1 by IFNa may be a key mechanism of improvement in fibrosis frequently observed in patients treated with IFNa.”
From Type 1 interferon perturbates clonal competition by reshaping human blood development (2026) · cites this paper as [51]
The citation in the printed sentence follows the claim that MPN megakaryocytes have higher TGFB1 expression; the IFNa–fibrosis mechanism is the citing authors’ subsequent inference. Our copy’s PAK4-inhibition section (pp. 20–21) discusses hematopoietic stem-cell cycling, not either TGFB1 expression in MPN megakaryocytes or IFNa-associated fibrosis improvement. Searches for TGFB1, MPN megakaryocytes, and IFNa found no passage addressing those points. (LLM, conf=0.72)
Experimental — accuracy not yet measuredTGFB1 was downregulated upon IFNa treatment.
“We also observed a downregulation of TGFB1 ( Supplementary Fig. 4b ), that encodes the pro-fibrotic cytokine TGFb established as one of the main inducers of myelofibrosis in patients with fibrotic-phase of MPN 50,51 .”
From Type 1 interferon perturbates clonal competition by reshaping human blood development (2026) · cites this paper as [51]
The cited paper’s PAK4-inhibition section (pp. 20–21) discusses hematopoietic stem-cell responses to a PAK4 inhibitor, not IFNα treatment. Searches for TGFB1 downregulation and IFNα treatment found no passage addressing the claim. In the citing sentence, references 50 and 51 appear attached to TGFβ’s role in myelofibrosis, while the downregulation is presented as the citing authors’ own observation. (LLM, conf=0.76)
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Cites
Batch effects in single-cell RNA-sequencing data are corrected by matching mutual nearest neighbors
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Histone Acetylation Regulates Intracellular pH
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Type 1 interferon perturbates clonal competition by reshaping human blood development
Lama, C., Isakov, D., Rosenberg, S., Quijada-Álamo, M., Saurty-Seerunghen, M. S., Moein, S., Nozais, M., Abera, T.-A., Sakaguchi, O., Totwani, M., et al. (2026) · Nature Genetics · doi:10.1038/s41588-026-02751-3 · Cited by 3 · see citing works
- Authors
- Kaufmann, K. B., Zeng, A. G. X., Coyaud, E., Garcia-Prat, L., Papalexi, E., Murison, A., Laurent, E. M. N., Chan-Seng-Yue, M., Gan, O. I., Pan, K., McLeod, J., Boutzen, H., Zandi, S., Takayanagi, S.-I., Satija, R., Raught, B., Xie, S. Z., & Dick, J. E.
- Affiliations
- University Health Network (CA)
- New York Genome Center (US)
- Corresponding author
- Dick, John E.
- ORCID
- Venue
- Nature Immunology
- Published
- 2021-05-06
- Volume
- 22
- Issue
- 6
- Pages
- 723-734
- ISSN
- 1529-2908 (ISSN-L)
- 1529-2916
- OpenAlex
- W3159593160
- Cited by
- 68
- References
- 6
- Citations by year
- 2026: 9 · 2025: 21 · 2024: 12 · 2023: 12 · 2022: 12 · 2021: 1 · 2020: 1
- FWCI
- 6.06
- Type
- journal article
- Language
- en
- Open access
- green
- lilloa.hal.science
- Licence
- Locations
- Nature Immunology (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion, other-oa)
- LillOA (Université de Lille (University Of Lille)) (submittedVersion, other-oa)
- Funders
- Canadian Institutes of Health Research (154293)
- Topics
- Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
- Health Sciences › Medicine › Genetics › Mesenchymal stem cell research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Blood disorders and treatments
- Keywords
- hematopoietic stem cells, long-term hematopoietic stem cells, HSC heterogeneity, CD112, SIRT1, PAK4, HSC quiescence, HSC self-renewal, histone H4K16 acetylation, epigenetic regulation, engraftment
- MeSH terms
- Cell Self Renewal, Immune Reconstitution, Nectins, RNA-Seq, Adult, Animals, Cells, Cultured, Female, Fetal Blood, Flow Cytometry, Hematopoiesis, Hematopoietic Stem Cells, Humans, Infant, Newborn, Male, Middle Aged, Stress, Physiological, Transplantation, Heterologous, Immunomagnetic Separation, Hematopoietic Stem Cell Transplantation, Multipotent Stem Cells, Epigenesis, Genetic, Intracellular Signaling Peptides and Proteins, Mice, p21-Activated Kinases, Gene Knockdown Techniques, Sirtuin 1, Single-Cell Analysis, Primary Cell Culture
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