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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Cell intrinsic alterations underlie hematopoietic stem cell aging
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Cell intrinsic alterations underlie hematopoietic stem cell aging

机译：细胞内在变化是造血干细胞衰老的基础

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摘要

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.
机译：免疫功能丧失和髓样白血病的发生率增加是造血系统衰老的临床上最重要的两个后果。为了更好地了解造血细胞衰老的潜在机制，我们评估了来自年轻和老年小鼠的高度纯化的长期造血干细胞（LT-HSC）的细胞内在功能和分子特性。我们发现LT-HSC衰老伴随着细胞自主性改变，包括干细胞自我更新增加，产生定型的髓样和淋巴样祖细胞的能力不同以及淋巴样潜能降低。表达谱显示，LT-HSC衰老伴随着介导淋巴样功能和功能的基因的系统性下调，以及涉及髓样命运和功能的基因的上调。此外，来自年老小鼠的LT-HSC表达了参与白血病转化的许多基因的升高水平。这些数据支持了这样一种模型，在该模型中，干细胞水平上基因表达的年龄依赖性改变预示了下游的发展潜力，从而促进了年龄依赖性免疫功能下降，并可能还导致了老年人白血病的发病率上升。

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