Conboy Michael J, Karasov Ariela O, Rando Thomas A
Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California, United States of America.
PLoS Biol. 2007 May;5(5):e102. doi: 10.1371/journal.pbio.0050102.
Decades ago, the "immortal strand hypothesis" was proposed as a means by which stem cells might limit acquiring mutations that could give rise to cancer, while continuing to proliferate for the life of an organism. Originally based on observations in embryonic cells, and later studied in terms of stem cell self-renewal, this hypothesis has remained largely unaccepted because of few additional reports, the rarity of the cells displaying template strand segregation, and alternative interpretations of experiments involving single labels or different types of labels to follow template strands. Using sequential pulses of halogenated thymidine analogs (bromodeoxyuridine [BrdU], chlorodeoxyuridine [CldU], and iododeoxyuridine [IdU]), and analyzing stem cell progeny during induced regeneration in vivo, we observed extraordinarily high frequencies of segregation of older and younger template strands during a period of proliferative expansion of muscle stem cells. Furthermore, template strand co-segregation was strongly associated with asymmetric cell divisions yielding daughters with divergent fates. Daughter cells inheriting the older templates retained the more immature phenotype, whereas daughters inheriting the newer templates acquired a more differentiated phenotype. These data provide compelling evidence of template strand co-segregation based on template age and associated with cell fate determination, suggest that template strand age is monitored during stem cell lineage progression, and raise important caveats for the interpretation of label-retaining cells.
几十年前，“不朽链假说”被提出，作为干细胞可能限制获得可能引发癌症的突变，同时在生物体的生命周期内持续增殖的一种方式。该假说最初基于对胚胎细胞的观察，后来从干细胞自我更新的角度进行研究，但由于额外的报道较少、显示模板链分离的细胞罕见，以及对涉及单一标记或不同类型标记以追踪模板链的实验存在其他解释，该假说在很大程度上未被接受。我们使用卤代胸腺嘧啶类似物（溴脱氧尿苷 [BrdU]、氯脱氧尿苷 [CldU] 和碘脱氧尿苷 [IdU]）的连续脉冲，并在体内诱导再生过程中分析干细胞后代，我们观察到在肌肉干细胞增殖扩张期间，较老和较年轻模板链的分离频率异常高。此外，模板链共分离与产生具有不同命运的子代的不对称细胞分裂密切相关。继承较老模板的子代细胞保留了更不成熟的表型，而继承较新模板的子代细胞获得了更分化的表型。这些数据提供了基于模板年龄且与细胞命运决定相关的模板链共分离的有力证据，表明在干细胞谱系进展过程中会监测模板链的年龄，并对标记保留细胞的解释提出了重要的注意事项。
