Abstract
BackgroundImmunologic aging leads to immune dysfunction, significantly reducing the quality of life of the elderly. Aged-related defects in early hematopoiesis result in reduced lymphoid cell development, functionally defective mature immune cells, and poor protective responses to vaccines and pathogens. Despite considerable progress understanding the underlying causes of decreased immunity in the elderly, the mechanisms by which these occur are still poorly understood. The DNA-binding protein ARID3a is expressed in a subset of human hematopoietic progenitors. Inhibition of ARID3a in bulk human cord blood CD34+ hematopoietic progenitors led to developmental skewing toward myeloid lineage at the expense of lymphoid lineage cells in vitro. Effects of ARID3a expression in adult-derived hematopoietic stem cells (HSCs) have not been analyzed, nor has ARID3a expression been assessed in relationship to age. We hypothesized that decreases in ARID3a could explain some of the defects observed in aging.ResultsOur data reveal decreased frequencies of ARID3a-expressing peripheral blood HSCs from aged healthy individuals compared with young donor HSCs. Inhibition of ARID3a in young donor-derived HSCs limits B lineage potential, suggesting a role for ARID3a in B lymphopoiesis in bone marrow-derived HSCs. Increasing ARID3a levels of HSCs from aged donors in vitro alters B lineage development and maturation. Finally, single cell analyses of ARID3a-expressing HSCs from young versus aged donors identify a number of differentially expressed genes in aged ARID3A-expressing cells versus young ARID3A-expressing HSCs, as well as between ARID3A-expressing and non-expressing cells in both young and aged donor HSCs.ConclusionsThese data suggest that ARID3a-expressing HSCs from aged individuals differ at both molecular and functional levels compared to ARID3a-expressing HSCs from young individuals.
Highlights
Immunologic aging leads to immune dysfunction, significantly reducing the quality of life of the elderly
We found that ARID3a is variably expressed in healthy human hematopoietic stem and progenitor cells (HSPCs), including total CD34+ HSPCs, hematopoietic stem cells (HSCs), multipotent progenitor (MPP), multi-lymphoid progenitors (MLP), and multi-myeloid progenitors (MMP) derived from adult peripheral blood [29], but the functional significance of expression in those progenitors is not clear
The data presented here suggest that HSCs from both aged and young donors contain equivalent numbers of ARID3a-expressing cells, total frequencies of ARID3a + cells were reduced in aged individuals
Summary
Immunologic aging leads to immune dysfunction, significantly reducing the quality of life of the elderly. A major consequence of aging is a decline in immune function Both murine and human studies revealed age-related defects in early hematopoietic development, and functional defects in mature immune cell populations, that result in decreased potentials to mount protective immune responses in aged individuals (reviewed in [2]), as exemplified by increased susceptibility to influenza and pneumonia in the elderly. Cells in the hematopoietic progenitor pool accumulate decreased telomere lengths and DNA damage markers, and their developmental potential becomes increasingly skewed toward myeloid versus lymphoid lineage development [6,7,8,9]. Identification of the changes in old age that alter the development of mature immune cells, and possibly contribute to their dysfunction, will require mechanistic studies that better define potential differences in gene regulatory mechanisms critical for lineage choices
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