Immunologic 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. Our 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. These data suggest that ARID3a-expressing HSCs from aged individuals differ at both molecular and functional levels compared to ARID3a-expressing HSCs from young individuals.

中文翻译：

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人类造血干细胞中的 ARID3a 表达与老年人不同的基因模式有关。

免疫老化导致免疫功能障碍，显着降低老年人的生活质量。早期造血中与年龄相关的缺陷导致淋巴细胞发育减少、成熟免疫细胞功能缺陷以及对疫苗和病原体的保护反应差。尽管在了解老年人免疫力下降的根本原因方面取得了相当大的进展，但这些发生的机制仍然知之甚少。DNA 结合蛋白 ARID3a 在人类造血祖细胞的一个子集中表达。在大量人脐带血 CD34+ 造血祖细胞中抑制 ARID3a 会导致在体外以淋巴系细胞为代价而向骨髓系发育倾斜。尚未分析 ARID3a 在成人造血干细胞 (HSC) 中表达的影响，也没有评估 ARID3a 表达与年龄的关系。我们假设 ARID3a 的降低可以解释在老化过程中观察到的一些缺陷。我们的数据显示，与年轻供体 HSC 相比，来自老年健康个体的表达 ARID3a 的外周血 HSC 的频率降低。在年轻的供体来源的 HSC 中抑制 ARID3a 会限制 B 谱系的潜力，这表明 ARID3a 在骨髓来源的 HSC 中 B 淋巴细胞生成中的作用。在体外增加老年供体 HSC 的 ARID3a 水平会改变 B 谱系的发育和成熟。最后，对来自年轻和老年供体的表达 ARID3a 的 HSC 的单细胞分析确定了表达 ARID3A 的老年细胞与表达年轻 ARID3A 的 HSC 中的许多差异表达基因，以及在年轻和老年供体 HSC 中表达 ARID3A 的细胞和不表达 ARID3A 的细胞之间。这些数据表明，与来自年轻人的表达 ARID3a 的 HSC 相比，来自老年人的表达 ARID3a 的 HSC 在分子和功能水平上都不同。