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Cited by 674Hematopoietic Stem Cell TransplantationRNA and protein synthesis mechanismsBiochemical and Molecular Research

Haematopoietic stem cells require a highly regulated protein synthesis rate

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Signer, Robert A. J., Magee, Jeffrey A., Salic, Adrian, Morrison, Sean J.·2014·Nature
DOI 10.1038/nature13035PMC PMC4015626
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Abstract

Many aspects of cellular physiology remain unstudied in somatic stem cells, for example, there are almost no data on protein synthesis in any somatic stem cell. Here we set out to compare protein synthesis in haematopoietic stem cells (HSCs) and restricted haematopoietic progenitors. We found that the amount of protein synthesized per hour in HSCs in vivo was lower than in most other haematopoietic cells, even if we controlled for differences in cell cycle status or forced HSCs to undergo self-renewing divisions. Reduced ribosome function in Rpl24(Bst/+) mice further reduced protein synthesis in HSCs and impaired HSC function. Pten deletion increased protein synthesis in HSCs but also reduced HSC function. Rpl24(Bst/+) cell-autonomously rescued the effects of Pten deletion in HSCs; blocking the increase in protein synthesis, restoring HSC function, and delaying leukaemogenesis. Pten deficiency thus depletes HSCs and promotes leukaemia partly by increasing protein synthesis. Either increased or decreased protein synthesis impairs HSC function.

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  • puro incorporation rates in HSCLT, SLAM cells, and MPP4 were all similar.

    “Consistent with prior work (Signer et al., 2014), puro incorporation rates in HSCLT, SLAM cells, and MPP4 were all similar (Fig. S1 G)”

    From PU.1 enforces quiescence and limits hematopoietic stem cell expansion during inflammatory stress (2021) · cites this paper as Signer et al., 2014

    In “HSCs synthesize less protein per hour” (page unavailable), the paper reports similar OP-Puro incorporation in CD150−CD48−LSK MPPs and CD150+CD48−LSK HSCs. It does not separately report incorporation rates for the specifically named HSCLT, SLAM, and MPP4 populations, so it supports the general comparison but not the claim at that level of specificity. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • Fine tuning of protein synthesis is essential for maintaining HSC quiescence and function.

    “Together, these data suggest that fine tuning of protein synthesis is essential for maintaining HSC quiescence and function (Signer et al., 2014).”

    From PU.1 enforces quiescence and limits hematopoietic stem cell expansion during inflammatory stress (2021) · cites this paper as Signer et al., 2014

    The Abstract reports that either increasing or decreasing protein synthesis impairs HSC function, supporting the need for a regulated rate. But the paper does not establish that fine-tuning protein synthesis maintains HSC quiescence; the “Even dividing HSCs make less protein” section shows that low synthesis is not limited to nondividing HSCs. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Deletion of Pten leads to aberrant HSC activity and hypersensitivity to inflammatory factors such as G-CSF and IFN.

    “deletion of Pten, which dephosphorylates and inhibits the eIF activator mammalian target of rapamycin, leads to similar aberrant HSC activity and hypersensitivity to inflammatory factors, such as G-CSF and IFN (Porter et al., 2016; Signer et al., 2014)”

    From PU.1 enforces quiescence and limits hematopoietic stem cell expansion during inflammatory stress (2021) · cites this paper as Signer et al., 2014

    In “Pten deletion increases protein synthesis” (page unavailable), the paper reports increased protein synthesis and depletion of HSCs after Pten deletion, supporting aberrant HSC activity. It does not report that Pten-deficient HSCs are hypersensitive to G-CSF or IFN; its G-CSF results concern Rpl24-mutant HSCs. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • HSCs carrying a hypomorphic allele of the ribosomal protein Rpl24 exhibit decreased proliferative activity and can rescue the phenotype of Pten-deficient HSCs.

    “HSCs carrying a hypomorphic allele of the ribosomal protein Rpl24 exhibit decreased proliferative activity and can rescue the phenotype of Pten-deficient HSCs (Signer et al., 2014).”

    From PU.1 enforces quiescence and limits hematopoietic stem cell expansion during inflammatory stress (2021) · cites this paper as Signer et al., 2014

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Cites

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Cited by

Sorted by citations

Authors
Signer, R. A. J., Magee, J. A., Salic, A., & Morrison, S. J.
Affiliations
  • Howard Hughes Medical Institute (US)
  • Harvard University (US)
Corresponding author
Morrison, Sean J.
ORCID
Venue
Nature
Publisher
Springer Science and Business Media LLC
Published
2014-03-09
Volume
509
Issue
7498
Pages
49-54
ISSN
  • 0028-0836 (ISSN-L)
  • 1476-4687
DOI
10.1038/nature13035
PMC
PMC4015626
OpenAlex
W2074670317
Cited by
674
References
5
Citations by year
2026: 38 · 2025: 63 · 2024: 75 · 2023: 65 · 2022: 74 · 2021: 70 · 2020: 67 · 2019: 52 · 2018: 54 · 2017: 39 · 2016: 31 · 2015: 37 · 2014: 8
FWCI
27.19
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
  • RePEc: Research Papers in Economics (submittedVersion)
Funders
  • Howard Hughes Medical Institute
  • Canadian Institutes of Health Research (106993_1)
  • National Institute on Aging (R37AG024945)
  • National Institute of Diabetes and Digestive and Kidney Diseases (R01DK100848)
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (K12HD068369)
Topics
  • Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Biochemical and Molecular Research
Keywords
hematopoietic stem cells, protein synthesis rate, ribosome function, PTEN deletion, leukemogenesis, HSC maintenance, cellular homeostasis, hematopoietic progenitor cells, self-renewal
MeSH terms
Animals, Cell Transformation, Neoplastic, Female, Flow Cytometry, Genetic Complementation Test, Hematopoietic Stem Cells, Homeostasis, Kinetics, Leukemia, Male, Mutation, Puromycin, Ribosomal Proteins, Ribosomes, Time Factors, Protein Biosynthesis, Proteasome Endopeptidase Complex, Cell Proliferation, PTEN Phosphohydrolase, Mice

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