ArticleNature2014
Replication stress is a potent driver of functional decline in ageing haematopoietic stem cells.
Article in Nature, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 412 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
412 citing papers in PubMed, 623 citations in OpenAlex.
- Mechanisms of Hematopoietic Stem Cell Aging and Emerging Rejuvenation Strategies.Stem cell reviews and reports · 2026Review
- In-depth characterization of stem cell potency and genotoxicity for clinical-scaleMolecular therapy. Advances · 2026Article
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- Hematopoietic Stem Cell Metabolism during Stress and Aging.Advances in geriatric medicine and research · 2026Article
- Article
- Geneformer-guided multiomics integration identifies Pbx1 as a network hub of hematopoietic stem cell aging.Science advances · 2026Article
- Single-Cell Analyses Reveal Dysregulation of Ribosomal Protein Genes During Hematopoietic Stem and Progenitor Cell Aging.Advanced biology · 2026Article
- IDEAL-Age: an interpretable deep learning framework for single-cell resolution profiling of immunological aging.Genome biology · 2026Article
- Inhibition of inflammation and senescence with azole compound C7 enables expansion of hematopoietic stem and progenitor cells.Stem cells translational medicine · 2026Article
- From complexity to clarity: aging bone marrow niche in bone and blood regeneration and malignancy.Bone research · 2026Review
- Hematopoietic Aging and Leukemia: Mechanistic and Therapeutic Insights.International journal of molecular sciences · 2026Review
- Subtle-seq reveals frequent ageing-associated chromosome fragmentation on nucleosome core DNA.Nucleic acids research · 2026Article
- Non-necroptotic MLKL function damages mitochondria and promotes hematopoietic stem cell aging.Nature communications · 2026Article
- Unlocking the HOX: Homeobox Genes as Regulators of Hematopoietic Development.International journal of molecular sciences · 2026Review
- Emerging Cardiovascular Risk Factors in Chronic Kidney Disease in the "Omics" Era: Gut and Beyond.Mayo Clinic proceedings · 2026Review
- Repeated proliferative events ameliorate age-associated accumulation of DNA damage in HSPCs.Life science alliance · 2026Article
- Age-Like Methylation Changes of HSCs in GADD45B Knockout Mice Define Methylation Sites Associated With Loss of Function.Aging cell · 2026Article
- Ribosome transfer via tunnelling nanotubes rescues protein synthesis in pancreatic cancer cells.Cell communication and signaling : CCS · 2026Article
- Spontaneous aging-associated inflammation and genome instability in the immune system of turquoise killifish.Nature aging · 2026Article
- Hematopoietic stem cell aging promotesResearch square · 2026Article
352 more citing papers are in PubMed but not listed here.
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Authors and funding
15 authors at 5 institutions in 3 countries.
Funding
Abstract
Haematopoietic stem cells (HSCs) self-renew for life, thereby making them one of the few blood cells that truly age. Paradoxically, although HSCs numerically expand with age, their functional activity declines over time, resulting in degraded blood production and impaired engraftment following transplantation. While many drivers of HSC ageing have been proposed, the reason why HSC function degrades with age remains unknown. Here we show that cycling old HSCs in mice have heightened levels of replication stress associated with cell cycle defects and chromosome gaps or breaks, which are due to decreased expression of mini-chromosome maintenance (MCM) helicase components and altered dynamics of DNA replication forks. Nonetheless, old HSCs survive replication unless confronted with a strong replication challenge, such as transplantation. Moreover, once old HSCs re-establish quiescence, residual replication stress on ribosomal DNA (rDNA) genes leads to the formation of nucleolar-associated γH2AX signals, which persist owing to ineffective H2AX dephosphorylation by mislocalized PP4c phosphatase rather than ongoing DNA damage. Persistent nucleolar γH2AX also acts as a histone modification marking the transcriptional silencing of rDNA genes and decreased ribosome biogenesis in quiescent old HSCs. Our results identify replication stress as a potent driver of functional decline in old HSCs, and highlight the MCM DNA helicase as a potential molecular target for rejuvenation therapies.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.