Persistent degenerative changes in thymic organ function revealed by an inducible model of organ regrowth.
Persistent degenerative changes in thymic organ function revealed by an inducible model of organ regrowth.
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DOI：
10.1111/j.1474-9726.2011.00773.x
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发表时间：
2012-02
期刊：
影响因子：
7.8
通讯作者：
Petrie HT
中科院分区：
文献类型：
--
作者：
Griffith AV;Fallahi M;Venables T;Petrie HT
胸腺是身体中老化最快的组织，早在出生时就开始进行性萎缩，不迟于青春期。潜在的再生潜力存在于萎缩的胸腺，因为某些刺激可以诱导定量再生，但由再生器官产生的T淋巴细胞的定性功能尚未得到充分评估。使用全基因组的计算方法，我们表明，加速胸腺衰老主要是一个功能的基质细胞，而整体细胞的胸腺可以恢复，胸腺功能的许多其他方面不能。髓质胰岛的复杂性和组织限制性抗原表达随年龄的增长而降低，代表了自身免疫性疾病中年龄相关性增加的潜在机制，但这两种机制都不能通过诱导再生来恢复，这表明再生胸腺产生的新T细胞可能包括更多的自身反应性细胞。基质基因表达谱的全球分析表明，Wnt信号的广泛变化是退化的最重要标志，即使在再生高峰期也会再次持续变化。与基质细胞中与年龄相关的分子变化的永久性一致，诱导的胸腺再生是不持久的，再生的器官在达到峰值大小的两周内恢复到萎缩状态。我们的研究结果表明，虽然胸腺的定量再生是可以实现的，但与衰老相关的变化仍然存在，包括对自身免疫的潜在负面影响。
The thymus is the most rapidly aging tissue in the body, with progressive atrophy beginning as early as birth and not later than adolescence. Latent regenerative potential exists in the atrophic thymus, since certain stimuli can induce quantitative regrowth, but qualitative function of T lymphocytes produced by the regenerated organ has not been fully assessed. Using a genome-wide computational approach, we show that accelerated thymic aging is primarily a function of stromal cells, and that while overall cellularity of the thymus can be restored, many other aspects of thymic function cannot. Medullary islet complexity and tissue-restricted antigen expression decrease with age, representing potential mechanisms for age-related increases in autoimmune disease, but neither of these is restored by induced regrowth, suggesting that new T cells produced by the regrown thymus will probably include more autoreactive cells. Global analysis of stromal gene expression profiles implicates widespread changes in Wnt signaling as the most significant hallmark of degeneration, changes that once again persist even at peak regrowth. Consistent with the permanent nature of age-related molecular changes in stromal cells, induced thymic regrowth is not durable, with the regrown organ returning to an atrophic state within two weeks of reaching peak size. Our findings indicate that while quantitative regrowth of the thymus is achievable, the changes associated with aging persist, including potential negative implications for autoimmunity.