TNF-α Coordinates Hematopoietic Stem Cell Survival and Myeloid Regeneration
Open accessAbstract
Inflammation coordinates tissue regeneration via damaged cell removal and stem cell activation. Hematopoietic stem cells (HSCs) survive inflammatory stress that kills other blood cells, but the mechanisms underlying this effect remain poorly understood. Here, we find that tumor necrosis factor α (TNF-α) acts differently on HSCs and progenitors, thus facilitating hematopoietic clearance and promoting regeneration. We show that while inducing myeloid progenitor apoptosis, TNF-α promotes HSC survival and myeloid differentiation by activating a strong and specific p65-nuclear factor κB (NF-κB)-dependent gene program that primarily prevents necroptosis rather than apoptosis, induces immunomodulatory functions, and poises HSCs for myeloid cell production. These TNF-α-driven mechanisms are critical for HSC response to inflammatory stress but are also hijacked in aged and malignant HSCs. Our results reveal several TNF-α-mediated pro-survival mechanisms unique to HSCs, highlight an important role for necroptosis in HSC killing, and establish TNF-α as a major pro-survival and pro-regeneration factor for HSCs.
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Analysis of HSCs from PU.1-EYFP mice treated acutely with TLR3 and -4 ligands polyriboinosinic: polyryibocyticylic acid and LPS, respectively, show that PU.1 is induced via a TNF-dependent mechanism.
“analysis of HSCs from PU.1-EYFP mice treated acutely with TLR3 and -4 ligands polyriboinosinic: polyryibocyticylic acid and LPS, respectively, show that PU.1 is induced via a TNF-dependent mechanism (Etzrodt et al., 2019; Yamashita and Passegué, 2019).”
From PU.1 enforces quiescence and limits hematopoietic stem cell expansion during inflammatory stress (2021) · cites this paper as Yamashita and Passegué, 2019
The Results section (“TNFα drives myeloid regeneration from HSCs”; page unavailable) reports increased PU.1 in HSCs from PU.1-eYFP mice after TNFα treatment. A separate Results section reports TNF-dependent responses to repeated pIC treatment and HSC loss after a 48-hour LPS challenge, but does not show PU.1 induction in PU.1-eYFP mice acutely treated with either ligand. (LLM, conf=0.88)
Experimental — accuracy not yet measuredThe mechanism of IL-1β-driven upregulation of Spi1 may be driven by pathways such as NF-κB.
“the mechanism of IL-1β-driven upregulation of Spi1 may be driven by pathways such as NF-κB (Pietras et al., 2016; Etzrodt et al., 2019; Yamashita and Passegue, 2019; Ahmed et al., 2022)”
From PU.1 is required to restrain myelopoiesis during chronic inflammatory stress (2023) · cites this paper as Yamashita and Passegue, 2019
The Discussion says PU.1 activation has been observed with IL-1, and the Results describe IL-1 signaling as a known NF-κB inducer. But the paper does not link NF-κB to IL-1-driven PU.1/Spi1 upregulation; in its pIC inflammation experiments, it identifies TNFα rather than IL-1 as the main driver of NF-κB activation. (LLM, conf=0.84)
Experimental — accuracy not yet measuredNF-κB is crucial for PU.1 induction in HSC.
“which we and others previously showed to be crucial for PU.1 induction in HSC.”
From PU.1 is required to restrain myelopoiesis during chronic inflammatory stress (2023) · cites this paper as Yamashita and Passegue, 2019
The Discussion reports that TNFα activates PU.1 in HSCs and drives p65/NF-κB activation during inflammation. The Results establish that NF-κB is crucial for HSC survival after TNFα exposure, but the passages do not establish that NF-κB is crucial for PU.1 induction. (LLM, conf=0.83)
Experimental — accuracy not yet measuredPU.1 plays a key role in emergency myelopoiesis.
“We and others have shown that PU.1 plays a key role in this process (Pietras et al., 2016; Yamashita and Passegue, 2019; Hernandez et al., 2020; Rabe et al., 2020; Chavez et al., 2021; Ahmed et al., 2022; Chavez et al., 2022).”
From PU.1 is required to restrain myelopoiesis during chronic inflammatory stress (2023) · cites this paper as Yamashita and Passegue, 2019
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Cites
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“…et al., 2022), which we and others previously showed to be crucial for PU.1 induction in HSC. Increased PU.1 expression in may also occur in PU.1KI/KI MPPGM via CEBPA-mediated transduction, as CEBPA binds to and induces Spi1 expression in HSPC (Kummalue and Friedman, 2003; Yeamans et al., 2007).”
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- Authors
- Yamashita, M., & Passegué, E.
- Affiliations
- Columbia University Irving Medical Center (US)
- ORCID
- Yamashita, Masayuki
- Venue
- Cell Stem Cell
- Publisher
- Elsevier BV
- Published
- 2019-09
- Volume
- 25
- Issue
- 3
- Pages
- 357-372.e7
- ISSN
- 1875-9777 (ISSN-L)
- 1934-5909
- PMC
- PMC6733032
- OpenAlex
- W2950532812
- Cited by
- 387
- References
- 6
- Citations by year
- 2026: 37 · 2025: 57 · 2024: 60 · 2023: 72 · 2022: 62 · 2021: 55 · 2020: 38 · 2019: 5
- FWCI
- 28.27
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell stem cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- University of California, San Francisco (Ripk3−/−)
- Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California Los Angeles
- National Institutes of Health
- Department of Medicine, Georgetown University (CA 94143)
- National Cancer Institute (2R01HL092471, P30CA013696, R01HL111266, R35HL135763)
- Japan Society for the Promotion of Science
- University of California, Los Angeles
- Vanderbilt University
- Topics
- Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Blood disorders and treatments
- Health Sciences › Medicine › Genetics › Mesenchymal stem cell research
- Keywords
- TNF-α, hematopoietic stem cells, inflammation, necroptosis, apoptosis, NF-κB p65, myeloid progenitor cells, myeloid differentiation, immunomodulation, aging
- MeSH terms
- Cell Self Renewal, Necroptosis, Animals, Cell Differentiation, Cell Survival, Gene Expression Regulation, Hematopoietic Stem Cells, Humans, Inflammation, Mice, Inbred C57BL, Regeneration, Tumor Necrosis Factor-alpha, NF-kappa B, Apoptosis, Mice, Knockout, Myeloid Cells, Mice, Immunomodulation
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