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Cell intrinsic alterations underlie hematopoietic stem cell aging
Open accessAbstract
Loss of immune function and an increased incidence of myeloid leukemia are two of the most clinically significant consequences of aging of the hematopoietic system. To better understand the mechanisms underlying hematopoietic aging, we evaluated the cell intrinsic functional and molecular properties of highly purified long-term hematopoietic stem cells (LT-HSCs) from young and old mice. We found that LT-HSC aging was accompanied by cell autonomous changes, including increased stem cell self-renewal, differential capacity to generate committed myeloid and lymphoid progenitors, and diminished lymphoid potential. Expression profiling revealed that LT-HSC aging was accompanied by the systemic down-regulation of genes mediating lymphoid specification and function and up-regulation of genes involved in specifying myeloid fate and function. Moreover, LT-HSCs from old mice expressed elevated levels of many genes involved in leukemic transformation. These data support a model in which age-dependent alterations in gene expression at the stem cell level presage downstream developmental potential and thereby contribute to age-dependent immune decline, and perhaps also to the increased incidence of leukemia in the elderly.
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“The age-related increase in expression of myeloid lineage genes in the studies noted above (11,17) likely resulted from the accumulation of myeloid-biased HSCs, as these analyses were performed on unseparated pools of HSCs.”
From Causes, consequences, and reversal of immune system aging (2013) · cites this paper as [11]
In the citing paper
“This shift has been correlated with increased expression of myeloid lineage genes and downregulation of those specifying a lymphoid lineage fate (11,17).”
From Causes, consequences, and reversal of immune system aging (2013) · cites this paper as [11]
In the citing paper
“The causes of this age-related reduction in lymphocyte development are multifactorial and include changes in HSCs and progenitor cells (11,12) as well as the local tissue and systemic environments (13,14).”
From Causes, consequences, and reversal of immune system aging (2013) · cites this paper as [11]
In the citing paper
“From an immunologic perspective, the most profound effect of stem cell aging in both mice (11,18) and humans (17) is a decreased capacity to produce lymphocytes and an increase in myeloid potential.”
From Causes, consequences, and reversal of immune system aging (2013) · cites this paper as [11]
In the citing paper
“young bone marrow cells, when transplanted into aged recipients, engraft worse than when transplanted into young recipients.”
From Aging of hematopoietic stem cells (2018) · cites this paper as [12]
In the citing paper
“examination of donor-derived reconstitution from old HSCs was significantly lower compared to the young with a marked myeloid bias lineage output”
From Quiescent Hematopoietic Stem Cells Accumulate DNA Damage during Aging that Is Repaired upon Entry into Cell Cycle (2014) · cites this paper as Rossi et al., 2005
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BackgroundMethodSelf-citationDNA Methylation in Cancer and Aging
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InfluentialHematopoietic stem cell niche maintenance during homeostasis and regeneration
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Human aging-associated DNA hypermethylation occurs preferentially at bivalent chromatin domainsPreprint
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“This age-associated lineage bias has been shown to result from age-dependent differences in the propensity of HSCs from young or old mice to commit and give rise to primitive oligo-potent myeloid or lymphoid progenitors (11, 14).”
BackgroundMethodResultInfluentialSelf-citationStem cells, ageing and the quest for immortality
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“Recently, direct molecular analysis of purified HS cells revealed differences in gene expression between cells from young and old mic”
BackgroundmTOR Regulation and Therapeutic Rejuvenation of Aging Hematopoietic Stem Cells
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Replication stress is a potent driver of functional decline in ageing haematopoietic stem cells
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BackgroundCdc42 activity regulates hematopoietic stem cell aging and rejuvenation
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InfluentialJNK Activity in Somatic Stem Cells Causes Loss of Tissue Homeostasis in the Aging Drosophila Gut
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BackgroundOxidative Stress in the Regulation of Normal and Neoplastic Hematopoiesis
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“lymphocyte ratio [25–29], a pattern consistent with our observation that granulocyte and T-lymphocyte specific genes were enriched”
BackgroundLifespan Extension by Preserving Proliferative Homeostasis in Drosophila
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“Specifically, the LT-HSC population (LSKCD342Flt32 or LSKCD482CD1501) accumulated with age, whereas the LSKCD341Flt31 population (containing lymphoid-primed multipotent progenitors [LMPPs]) decreased (supplemental Figure 1A), as previously described.(1) In young mice (aged 2 months), CD41 expression on LSKs was low (;…”
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“5 stem cells in bone marrow exhibit a myeloid-biased differentiation potential (12, 13), which 70 causes changes in the cell population of peripheral blood.”
BackgroundA Differentiation Checkpoint Limits Hematopoietic Stem Cell Self-Renewal in Response to DNA Damage
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Self-citationp53-Mediated Hematopoietic Stem and Progenitor Cell Competition
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“In addition, P-selectin and Sdpr, which are upregulated in aged HSCs (Chambers et al., 2007; Rossi et al., 2005), were also upregulated in loser and downregulated in winner HSPC cells (Figure 6B).”
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Chronic Exposure to a TLR Ligand Injures Hematopoietic Stem Cells
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“experiments, old HSCs transferred to young hosts retain their aged phenotype (Rossi et al., 2005), supporting the notion that HSC aging is largely driven by cell-intrinsic mechanisms.”
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A canonical to non-canonical Wnt signalling switch in haematopoietic stem-cell ageing
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“Hematopoietic aging is characterized by expansion of hematopoietic stem cells (HSCs) with impaired function, such as reduced engraftment, quiescence, self-renewal, unfolded protein response, and lymphoid differentiation potential, leading to myeloid-biased output both in mice (Liang et al., 2005; Mohrin et al., 2015;…”
BackgroundTNF-α–driven inflammation and mitochondrial dysfunction define the platelet hyperreactivity of aging
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The chronic myeloid leukemia stem cell: stemming the tide of persistence
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“and the detection of BCR-ABL1 in blood cells of normal individuals(26,27) present the possibility that heterogeneity could also be driven by mutations acquired before or after BCR-ABL1, or other factors such as deregulation and skewing of lineage specification, clonal hemopoiesis, DNA damage, activation of inflammator…”
BackgroundCell-cycle restriction limits DNA damage and maintains self-renewal of leukaemia stem cells
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BackgroundManifestations and mechanisms of stem cell aging
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“Hematopoietic stem cells (HSCs) from both old humans and old mice show an increased propensity to differentiate along the myeloid rather than the lymphoid lineage (Sudo et al., 2000; Rossi et al., 2005).”
Macrophage Related Chronic Inflammation in Non-Healing Wounds
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“, 1996) and altered cell fate decisions (Rossi et al., 2005; Sudo et al., 2000).”
BackgroundHematopoietic stem cells count and remember self-renewal divisions
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Rantes/Ccl5 influences hematopoietic stem cell subtypes and causes myeloid skewing
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“In the blood system, HSC numbers increase with age but HSC function declines (Morrison et al., 1996; Rossi et al., 2005), leading to impaired stem cell engraftment potential and skewed production of mature cell lineages by individual aged HSCs (Dykstra et al., 2011).”
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Gene Expression Commons: An Open Platform for Absolute Gene Expression Profiling
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“0 CD342 Flk22 KLS (young) CD342 Flk22 KLS (old) 45000 34000 [26]”
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“Aged murine haematopoietic stem cells (HSCs) exhibit a skewed differentiation potential toward the myeloid lineag”
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“The HSC compartment undergoes a range of functional and phenotypic alterations with age (Rossi et al., 2005).”
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Pbx1 Regulates Self-Renewal of Long-Term Hematopoietic Stem Cells by Maintaining Their Quiescence
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“ROSSI_AGING_UP 0.00 Upregulated in LT-HSCs from aging mice (= higher self-renewal) ( Rossi et al., 2005 )”
BackgroundInfluentialThe hematopoietic stem cell niche: from embryo to adult
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“Aged HSCs are more proliferative and their numbers increase in the aged bone marrow (de Haan et al., 1997; Dykstra et al., 2011; Morrison et al., 1996; Rossi et al., 2005).”
BackgroundIBD across the age spectrum—is it the same disease?
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Depleting myeloid-biased haematopoietic stem cells rejuvenates aged immunity
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Self-citationInsights into Mesenchymal Stem Cell Aging: Involvement of Antioxidant Defense and Actin Cytoskeleton
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Targeting immune dysfunction in aging
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“Indeed, in younger mice HSCs perform much better compared to older mice HSCs after transplantation, indicating higher potency (Dykstra et al., 2011; Rossi et al., 2005; Verovskaya et al., 2013).”
T cell regeneration after immunological injury
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Metadata
- Authors
- Rossi, D. J., Bryder, D., Zahn, J. M., Ahlenius, H., Sonu, R., Wagers, A. J., & Weissman, I. L.
- Affiliations
- Joslin Diabetes Center (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2005-06-20
- Volume
- 102
- Issue
- 26
- Pages
- 9194-9199
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC1153718
- OpenAlex
- W2131263031
- Cited by
- 1,152
- References
- 47
- Citations by year
- 2026: 44 · 2025: 56 · 2024: 49 · 2023: 55 · 2022: 56 · 2021: 80 · 2020: 57 · 2019: 71 · 2018: 57 · 2017: 59 · 2016: 67 · 2015: 54 · 2014: 56 · 2013: 63 · 2012: 55
- FWCI
- 24.68
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Lund University Publications (Lund University) (submittedVersion)
- Funders
- Damon Runyon Cancer Research Foundation
- National Institutes of Health
- Medical Research Council
- National Cancer Institute (R01CA086065)
- Topics
- Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Mesenchymal stem cell research
- Keywords
- hematopoietic stem cell aging, long-term hematopoietic stem cells, stem cell self-renewal, leukemic transformation, age-related immune decline, gene expression profiling
- MeSH terms
- Animals, Cell Separation, Cell Transformation, Neoplastic, Flow Cytometry, Gene Expression Regulation, Hematopoiesis, Hematopoietic Stem Cells, Leukemia, Mice, Inbred C57BL, Software, Stem Cells, Down-Regulation, Up-Regulation, Genome, Cellular Senescence, Cell Transplantation, Cell Lineage, Reverse Transcriptase Polymerase Chain Reaction, Oligonucleotide Array Sequence Analysis, Mice
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