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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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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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