Progressive telomere shortening occurs in cultured rat microglia, but not astrocytes
Progressive telomere shortening occurs in cultured rat microglia, but not astrocytes
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DOI：
10.1002/glia.10301
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发表时间：
2004-01-01
期刊：
影响因子：
6.2
通讯作者：
Streit, WJ
中科院分区：
文献类型：
--
作者：
Flanary, BE;Streit, WJ
正常的体细胞具有有限的复制能力。随着每次细胞分裂，端粒逐渐缩短，直到它们达到临界长度，在这一点上，细胞进入复制衰老。一些细胞通过端粒酶的作用来维持其端粒。胶质细胞，特别是小胶质细胞，是中枢神经系统(CNS)中唯一显示出显著有丝分裂潜力的成体细胞类型，因此对端粒缩短敏感。在这项研究中，我们发现，在体外培养的大鼠小胶质细胞中，端粒缩短伴随着低到中等的端粒酶活性，最终发生衰老。当小胶质细胞被刺激与有丝分裂原粒细胞巨噬细胞集落刺激因子(GM-CSF)分裂时，较长的端粒被允许缩短，而较短的端粒被延长。在GM-CSF刺激的小胶质细胞中，端粒酶活性最初比未刺激的对照组高近3倍，然后下降到低于对照组的水平，然后再次上升。当小胶质细胞生长在不断增大的培养皿中时，端粒的磨损也更快。荧光原位杂交(FISH)分析表明，在小胶质细胞中，染色体间和染色体内的端粒长度存在近3倍的差异。与小胶质细胞相比，培养的星形胶质细胞呈现出端粒随着时间的延长和缩短的周期性模式，对应着类似的端粒酶活性升高和降低的周期。当星形胶质细胞传代时，平均端粒长度从第1-2代开始增加，直到第5代保持不变，而最短的端粒不断延长。综上所述，小胶质细胞的端粒明显缩短伴随着其在体外32天内的衰老。相比之下，星形胶质细胞可能由于端粒酶活性更强，寿命更长，在进入衰老之前可能会反复传代。我们的发现为研究体内发生小胶质细胞端粒缩短的可能性提供了动力。(C)2003年Wiley-Liss，Inc.
Normal somatic cells have a finite replicative capacity. With each cell division, telomeres shorten progressively until they reach a critical length, at which point the cells enter replicative senescence. Some cells maintain their telomeres by the action of the telomerase enzyme. Glia, particularly microglia, are the only adult cell types in the central nervous system (CNS) that exhibit a significant mitotic potential, and are thus susceptible to telomere shortening. In this study, we show that telomere shortening accompanied by low to moderate telomerase activity, and ultimately senescence, occurs in rat microglia in vitro. When microglia are stimulated to divide with the mitogen granulocyte macrophage-colony stimulating factor (GM-CSF), longer telomeres are allowed to shorten, while shorter telomeres are lengthened. Telomerase activity is nearly 3-fold higher in GM-CSF-stimulated microglia initially, relative to unstimulated controls, and then declines to levels below those seen in controls before increasing again. Telomere attrition is also more rapid when microglia are grown in culture dishes of increasing size. Fluorescence in situ hybridization (FISH) analysis indicates that a nearly 3-fold variation in both inter- and intra-chromosomal telomere length exists in microglia. In contrast to microglia, cultured astrocytes exhibit a cyclical pattern of telomere lengthening and shortening over time, corresponding to a similar cycle of higher and lower telomerase activity. When astrocytes are passaged, mean telomere length increases initially from passage 1-2, remaining constant until passage 5, while the shortest telomeres are continually lengthened. In conclusion, the telomere shortening evident in microglia is accompanied by their progression to senescence by 32 days in vitro. In contrast, astrocytes, perhaps due to greater telomerase activity, have longer life spans and may be passaged repeatedly before entering senescence. Our findings provide an impetus to investigate the possibility that microglial telomere shortening may occur in vivo. (C) 2003 Wiley-Liss, Inc.