Interdepartmental Program of Developmental Biology, Baylor College of Medicine, One Baylor Plaza, N1030, Houston, TX 77030, USA.
Blood. 2012 Mar 15;119(11):2500-9. doi: 10.1182/blood-2011-11-391730. Epub 2012 Jan 30.
HSCs undergo dramatic changes with aging. An increase in absolute numbers of HSCs along with a functional deficit in reconstitution potential and a shift toward production of myeloid cells are the hallmarks of murine hematopoietic aging. Here, we show that high levels of the inflammatory cytokine Rantes are found in the aging stem cell milieu. Forced overproduction of Rantes by retroviral expression in BM progenitors resulted in a deficit of T-cell output, and brief ex vivo exposure of HSCs to Rantes resulted in a decrease in T-cell progeny concomitant with an increase in myeloid progenitors. In contrast, Rantes knockout (KO) animals exhibit a decrease in myeloid-biased HSCs and myeloid progenitors and an increase in T cells and lymphoid-biased HSCs. KO HSCs retained their HSC subtype distribution and they produced more lymphoid-biased HSCs in transplantations. Rantes deficiency also resulted in a decreased mammalian target of rapamycin (mTOR) activity in KLS cells. In a heterochronic transplantation setting, we further show that aged HSCs placed in a young environment generate less myeloid cells. These data establish a critical role for environmental factors in the establishment of the aged-associated myeloid skewing phenotype, which may contribute to age-associated immune deficiency.
造血干细胞（HSCs）随衰老发生显著改变。HSCs 数量绝对增加，重建潜能的功能缺陷，以及向髓系细胞生成的转变，这些都是鼠类造血衰老的特征。在这里，我们发现衰老的干细胞微环境中存在高水平的炎症细胞因子 Rantes。通过逆转录病毒在 BM 祖细胞中的过表达强制产生 Rantes，导致 T 细胞输出减少，而短暂的 HSCs 体外暴露于 Rantes 导致 T 细胞后代减少，同时髓系前体增加。相比之下，Rantes 敲除（KO）动物表现出髓系偏向 HSCs 和髓系前体减少，T 细胞和淋巴系偏向 HSCs 增加。KO HSCs 保留了其 HSC 亚型分布，并且在移植中产生了更多的淋巴系偏向 HSCs。Rantes 缺乏还导致 KLS 细胞中哺乳动物雷帕霉素靶蛋白（mTOR）活性降低。在异时性移植设置中，我们进一步表明，置于年轻环境中的衰老 HSCs 产生的髓系细胞较少。这些数据确立了环境因素在建立与衰老相关的髓系偏斜表型中的关键作用，这可能导致与年龄相关的免疫缺陷。
