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首页> 外文期刊>Journal of Pathology: Journal of the Pathological Society of Great Britain and Ireland >Analysis of the clonal architecture of the human small intestinal epithelium establishes a common stem cell for all lineages and reveals a mechanism for the fixation and spread of mutations.
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Analysis of the clonal architecture of the human small intestinal epithelium establishes a common stem cell for all lineages and reveals a mechanism for the fixation and spread of mutations.

机译：对人类小肠上皮细胞克隆结构的分析建立了所有谱系的共同干细胞，并揭示了固定和扩散突变的机制。

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Little is known about the clonal structure or stem cell architecture of the human small intestinal crypt/villus unit, or how mutations spread and become fixed. Using mitochondrial DNA (mtDNA) mutations as a marker of clonal expansion of stem cell progeny, we aimed to provide answers to these questions. Enzyme histochemistry (for cytochrome c oxidase and succinate dehydrogenase) was performed on frozen sections of normal human duodenum. Laser-capture microdissected cells were taken from crypts/villi. The entire mitochondrial genome was amplified using a nested PCR protocol; sequencing identified mutations and immunohistochemistry demonstrated specific cell lineages. Cytochrome c oxidase-deficient small bowel crypts were observed within all sections: negative crypts contained the same clonal mutation and all differentiated epithelial lineages were present, indicating a common stem cell origin. Mixed crypts were also detected, confirming the existence of multiple stem cells. We observed crypts where Paneth cells were positive but the rest of the crypt was deficient. We have demonstrated patches of deficient crypts that shared a common mutation, suggesting that they have divided by fission. We have shown that all cells within a small intestinal crypt are derived from one common stem cell. Partially-mutated crypts revealed some novel features of Paneth cell biology, suggesting that either they are long-lived or a committed Paneth cell-specific long-lived progenitor was present. We have demonstrated that mutations are fixed in the small bowel by fission and this has important implications for adenoma development.
机译：关于人类小肠隐窝/绒毛单元的克隆结构或干细胞结构，或突变如何扩散并固定，人们所知甚少。使用线粒体DNA（mtDNA）突变作为干细胞后代克隆扩增的标志物，我们旨在为这些问题提供答案。在正常人十二指肠的冷冻切片上进行酶组织化学（用于细胞色素C氧化酶和琥珀酸脱氢酶）。激光捕获的显微解剖细胞取自隐窝/绒毛。使用巢式PCR方案扩增整个线粒体基因组;测序鉴定出的突变和免疫组织化学证实了特定的细胞谱系。在所有切片中均观察到细胞色素C氧化酶缺陷的小肠隐窝：阴性隐窝包含相同的克隆突变，并且存在所有分化的上皮谱系，表明共有干细胞起源。还检测到混合隐窝，证实存在多个干细胞。我们观察到Paneth细胞阳性的隐窝，但其余隐窝均不足。我们已经展示了具有共同突变的缺陷隐窝的斑块，表明它们已被裂变分裂。我们已经表明，小肠隐窝内的所有细胞均来自一个常见的干细胞。部分突变的隐窝揭示了Paneth细胞生物学的一些新颖特征，这表明它们要么长寿，要么存在特定的Paneth细胞特异性长寿祖细胞。我们已经证明，突变通过裂变固定在小肠中，这对腺瘤的发展具有重要意义。

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