Cell intrinsic alterations underlie hematopoietic stem cell aging
Cell intrinsic alterations underlie hematopoietic stem cell aging
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DOI：
10.1073/pnas.0503280102
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发表时间：
2005-06-28
影响因子：
11.1
通讯作者：
Weissman, IL
中科院分区：
文献类型：
--
作者：
Rossi, DJ;Bryder, D;Weissman, IL
免疫功能丧失和髓系白血病发病率增加是造血系统老化的两个最显著的临床后果。为了更好地了解造血衰老的机制，我们评估了来自年轻和老年小鼠的高纯度长期造血干细胞(LT-HSCs)的细胞内在功能和分子特性。我们发现LT-HSC的老化伴随着细胞的自主性变化，包括干细胞自我更新增加，分化能力产生承诺的髓系和淋巴系前体细胞，以及淋巴系潜能降低。表达谱显示，LT-HSC的衰老伴随着调节淋巴系统规范和功能的基因的系统性下调，以及与髓系命运和功能相关的基因的上调。此外，来自老年小鼠的LT-HSCs表达了许多与白血病转化相关的基因水平升高。这些数据支持一种模型，在该模型中，干细胞水平上基因表达的年龄相关性变化预示着下游发育潜力，从而导致年龄相关性免疫功能下降，或许还会导致老年人白血病发病率的增加。
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.