Mitochondrial DNA mutations are established in human colonic stem cells, and mutated clones expand by crypt fission
Mitochondrial DNA mutations are established in human colonic stem cells, and mutated clones expand by crypt fission
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DOI：
10.1073/pnas.0505903103
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发表时间：
2006-01-17
影响因子：
11.1
通讯作者：
McDonald, SAC
中科院分区：
文献类型：
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作者：
Greaves, LC;Preston, SL;McDonald, SAC
理解人类组织内突变的固定及其随后的克隆扩增是一个相当大的问题，人们对此知之甚少。我们先前已经表明，线粒体基因组中的非致癌突变发生在一些形态正常的结肠隐窝干细胞中的一个，其后代后来占据整个隐窝。我们提出，这些完全突变的隐窝随后通过隐窝分裂进行克隆扩增，即每个隐窝分裂为两个突变的子隐窝。在此我们表明：（i）处于分裂过程中的突变隐窝具有相同的突变线粒体基因型，而相邻的细胞色素c氧化酶阳性隐窝中不存在这种基因型（这是随机事件的概率≥2.48×10⁹ : 1）；（ii）相邻的突变隐窝具有相同的基因型，且与相邻的细胞色素c氧化酶阳性隐窝不同；（iii）突变隐窝在整个结肠中聚集在一起；（iv）细胞色素c氧化酶缺陷隐窝的斑块随着年龄的增长而增大。因此，我们明确地证明了隐窝分裂是突变在正常人结肠中传播的机制。这对正常成年人结肠的生物学以及可能对结直肠肿瘤的生长和扩散具有重要意义。
The understanding of the fixation of mutations within human tissues and their subsequent clonal expansion is a considerable problem, of which little is known. We have previously shown that nononcogenic mutations in the mitochondrial genome occur in one of a number of morphologically normal colonic crypt stem cells, the progeny of which later occupy the whole crypt. We propose that these wholly mutated crypts then clonally expand by crypt fission, where each crypt divides into two mutated daughter crypts. Here we show that (i) mutated crypts in the process of fission share the same mutated mitochondrial genotype not present in neighboring cytochrome c oxidase-positive crypts (the odds of this being a random event are >= 2.48 x 10(9):1); (ii) neighboring mutated crypts have the same genotype, which is different from adjacent cytochrome c oxidase-positive crypts; (iii) mutated crypts are clustered together throughout the colon; and (iv) patches of cytochrome c oxidase-deficient crypts increase in size with age. We thus demonstrate definitively that crypt fission is the mechanism by which mutations spread in the normal human colon. This has important implications for the biology of the normal adult human colon and possibly for the growth and spread of colorectal neoplasms.