Declining expression of a single epithelial cell-autonomous gene accelerates age-related thymic involution.
Declining expression of a single epithelial cell-autonomous gene accelerates age-related thymic involution.
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DOI：
10.1111/j.1474-9726.2010.00559.x
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发表时间：
2010-06
期刊：
影响因子：
7.8
通讯作者：
Su DM
中科院分区：
文献类型：
--
作者：
Sun L;Guo J;Brown R;Amagai T;Zhao Y;Su DM
淋巴造血和/或非造血胸腺上皮细胞（TEC）的基因表达变化可能会触发胸腺退化。上皮细胞自主基因FoxN 1可能参与了这一过程，但由于缺乏功能逐渐丧失和外源性功能获得的研究证据，至今仍是一个谜。使用我们最近产生的loxP-floxed-FoxN 1（fx）小鼠携带普遍存在的CreERT（uCreERT）转基因，具有低剂量的自发激活，这会导致FoxN 1随着年龄的增长而逐渐缺失，我们发现uCreERT-fx/fx小鼠由于FoxN 1 + TEC的逐渐丧失而显示出与年龄相关的加速胸腺退化。胸腺老化表型早在3-6月龄时就可清楚观察到，类似于自然老化（18-22月龄）的小鼠胸腺。通过胸腺内提供外源性FoxN 1-cDNA的老年野生型小鼠，胸腺退化和缺陷的外周CD 4 + T细胞功能可以部分获救。这些结果支持了这样的观点，即随着年龄的增长，单个上皮细胞自主基因FoxN 1水平的下降会导致TEC的主要恶化，随后会损害出生后胸腺的总微环境，并可能引发小鼠与年龄相关的胸腺退化。
Age-related thymic involution may be triggered by gene expression changes in lymphohematopoietic and/or non-hematopoietic thymic epithelial cells (TECs). The role of epithelial cell-autonomous gene FoxN1 may be involved in the process, but it is still a puzzle due to shortage of evidence from gradual loss-of-function and exogenous gain-of-function studies. Using our recently generated loxP-floxed-FoxN1(fx) mouse carrying the ubiquitous CreERT (uCreERT) transgene with a low dose of spontaneous activation, which causes gradual FoxN1 deletion with age, we found that the uCreERT-fx/fx mice showed an accelerated age-related thymic involution due to progressive loss of FoxN1+ TECs. The thymic aging phenotypes were clearly observable as early as at 3–6 months of age, resembling the naturally aged (18–22-month-old) murine thymus. By intrathymically supplying aged wild-type mice with exogenous FoxN1-cDNA, thymic involution and defective peripheral CD4+ T-cell function could be partially rescued. The results support the notion that decline of a single epithelial cell-autonomous gene FoxN1 levels with age causes primary deterioration in TECs followed by impairment of the total postnatal thymic microenvironment, and potentially triggers age-related thymic involution in mice.