Aging Hematopoietic Stem Cells Decline in Function and Exhibit Epigenetic Dysregulation

By S. M. Chambers, Chad A. Shaw, Catherine E. Gatza, C. Fisk, L. Donehower, Margaret A. Goodell. PLoS Biology, 2007

804 citations recorded by the source corpus.

Age-related defects in stem cells can limit proper tissue maintenance and hence contribute to a shortened lifespan. Using highly purified hematopoietic stem cells from mice aged 2 to 21 mo, we demonstrate a deficit in function yet an increase in stem cell number with advancing age. Expression analysis of more than 14,000 genes identified 1,500 that were age-induced and 1,600 that were age-repressed. Genes associated with the stress response, inflammation, and protein aggregation dominated the up-regulated expression profile, while the down-regulated profile was marked by genes involved in the preservation of genomic integrity and chromatin remodeling. Many chromosomal regions showed coordinate loss of transcriptional regulation; an overall increase in transcriptional activity with age and inappropriate expression of genes normally regulated by epigenetic mechanisms was also observed. Hematopoietic stem cells from early-aging mice expressing a mutant p53 allele reveal that aging of stem cells can be uncoupled from aging at an organismal level. These studies show that hematopoietic stem cells are not protected from aging. Instead, loss of epigenetic regulation at the chromatin level may drive both functional attenuation of cells, as well as other manifestations of aging, including the increased propensity for neoplastic transformation.

Subfields: Hematology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/98535c6380a124e568a4d0d8913d1de63ccae9f6

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Human bone marrow hematopoietic stem cells are increased in frequency and myeloid-biased with age (2011, background): “Notably, the results from our functional analysis and gene expression profiling of young and elderly human HSC significantly parallel the data we and others have generated on young and elderly mouse HSC (2, 6, 36).”
Linking functional decline of telomeres, mitochondria and stem cells during ageing (2010, positive): “As they age, different tissues derived from these hyper- p53 mice develop increased numbers of senescent cells; furthermore, their HSCs exhibit decreased activity in competitive transplants, as well as decreased engraftment capacit”
Epigenomic profiling of young and aged HSCs reveals concerted changes during aging that reinforce self-renewal (2014, methodology): “…analysis with the Molecular Signature Database as well as several customized HSC, myeloid, and lymphoid gene sets (‘‘fingerprint’’ genes; Table S2) (Chambers et al., 2007a) revealed that HSC-specific genes as a group were upregulated in old HSCs, in agreement with their increased phenotypic…”
Stems cells and the pathways to aging and cancer. (2008, background): “, 2005), chromosomal regions (Chambers et al., 2007), and genes involved in chromatin remodeling (Chambers et al.”
Replicative Senescence of Mesenchymal Stem Cells: A Continuous and Organized Process (2008, background): “These epigenetic modifications have been postulated to play a role in senescence [13,52].”
Distinct Hematopoietic Stem Cell Subtypes Are Differentially Regulated by TGFβ1 (2010, positive): “…irradiated recipients in transplantation assays (Morrison et al., 1996; Liang et al., 2005), a vastly different gene expression profile (Rossi et al., 2005; Chambers et al., 2007), and a myeloid-differentiation bias compared to their young counterparts (Sudo et al., 2000; Kim et al., 2003).”
Functionally distinct hematopoietic stem cells modulate hematopoietic lineage potential during aging by a mechanism of clonal expansion (2010, background): “However, humoral factors originating from the aged micro- or systemic environments that appear to be related to chronic inflammationmight alsobe important inmodulatingHSCaging (32).”
Single-cell RNA-seq reveals changes in cell cycle and differentiation programs upon aging of hematopoietic stem cells (2015, background): “Previous transcriptional profiling limited to populations of young and old LT-HSCs demonstrated up-regulation of myeloid genes and down-regulation of lymphoid and cell cycle genes with age (Rossi et al. 2005; Chambers et al. 2007; Sun et al. 2014).”