Stochastic homeostasis in human airway epithelium is achieved by neutral competition of basal cell progenitors.
Stochastic homeostasis in human airway epithelium is achieved by neutral competition of basal cell progenitors.
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DOI：
10.7554/elife.00966
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发表时间：
2013-10-22
期刊：
影响因子：
7.7
通讯作者：
Janes SM
中科院分区：
文献类型：
--
作者：
Teixeira VH;Nadarajan P;Graham TA;Pipinikas CP;Brown JM;Falzon M;Nye E;Poulsom R;Lawrence D;Wright NA;McDonald S;Giangreco A;Simons BD;Janes SM
谱系追踪方法为支持小鼠组织稳态的细胞机制提供了新的见解。然而，这些发现与人类上皮稳态及其在疾病中的改变的相关性尚不清楚。通过开发一种新的定量方法来分析随着时间的推移而积累的体细胞线粒体突变，我们证明了人类上呼吸道上皮细胞是由等能的基底祖细胞群体维持的，其中由于谱系承诺而导致的细胞的机会损失通过邻居的重复得到完美补偿，导致克隆群体的“中性漂移”。此外，我们表明，这一过程在吸烟者的气道加速，导致加强克隆巩固和肿瘤发生提供了背景。这项研究提供了一个基准，以显示体细胞突变如何提供人体组织中稳态生长的定量信息，以及探索导致失调和疾病的因素的平台。DOI：http://dx.doi.org/10.7554/eLife.00966.001当空气流入我们的肺部时，鼻腔、喉咙和呼吸道其他部分的内壁会阻止微生物、细菌、灰尘和其他小颗粒进入肺部。这些气道的衬里由许多不同类型的细胞组成，当它们受损时必须不断更换。在小鼠身上的实验表明，称为基底细胞的细胞充当祖细胞，以保持内膜供应新细胞。祖细胞类似于干细胞：它们平均分裂为一个自身拷贝和一个另一种类型的成熟细胞（如分泌细胞）。这确保了祖细胞的健康供应在未来得以维持。然而，目前尚不清楚这一过程是否发生在单个祖细胞水平或作为细胞群体的平均水平。特谢拉等人现在已经进行了一项研究，该研究表明基底细胞作为平均化的结果而实现这种平衡。这项研究利用了一个事实，即称为线粒体的细胞器有自己的DNA，随着时间的推移逐渐积累突变。这使得有可能识别来自单个祖细胞的细胞群，因为它们都含有相同的线粒体突变。通过研究来自7个个体的肺组织，特谢拉等人能够识别相关细胞的簇，并发现，正如预期的那样，簇的大小随着年龄的增长而增加。通过在研究中的所有细胞中应用数学模型，发现每当一个基础祖细胞致力于特定的命运时，另一个祖细胞就会自我复制：然而，这种平衡过程以随机的方式发生在大量细胞中，而不是在单个祖细胞的水平上。有趣的是，研究发现吸烟者也会发生随机细胞分裂，但会加速。这导致吸烟者比非吸烟者更快地形成相同的细胞簇。除了提供对肺癌起源的进一步了解外，特谢拉等人开发的统计方法还可用于分析许多其他类型的干细胞或祖细胞的行为。DOI：http://dx.doi.org/10.7554/eLife.00966.002网站
Lineage tracing approaches have provided new insights into the cellular mechanisms that support tissue homeostasis in mice. However, the relevance of these discoveries to human epithelial homeostasis and its alterations in disease is unknown. By developing a novel quantitative approach for the analysis of somatic mitochondrial mutations that are accumulated over time, we demonstrate that the human upper airway epithelium is maintained by an equipotent basal progenitor cell population, in which the chance loss of cells due to lineage commitment is perfectly compensated by the duplication of neighbours, leading to “neutral drift” of the clone population. Further, we show that this process is accelerated in the airways of smokers, leading to intensified clonal consolidation and providing a background for tumorigenesis. This study provides a benchmark to show how somatic mutations provide quantitative information on homeostatic growth in human tissues, and a platform to explore factors leading to dysregulation and disease. DOI: http://dx.doi.org/10.7554/eLife.00966.001 As air flows into our lungs, the lining of the nasal cavity, the throat and the rest of the respiratory tract prevents microbes, bacteria, dust and other small particles from entering the lungs. The lining of these airways is made up of many different types of cells, which must be continuously replaced as they become damaged. Experiments in mice have shown that cells called basal cells act as progenitor cells to keep the lining supplied with new cells. Progenitor cells are similar to stem cells: they divide to make, on average, one copy of themselves and one mature cell of another type (such as a secretory cell). This ensures that healthy supply of progenitor cells is maintained for the future. However, it is not clear whether this process takes place at the level of individual progenitor cells or as an average for a population of cells. Teixeira et al. have now performed a study which shows that basal cells achieve this balance as a result of averaging. The study took advantage of the fact that cellular organelles called mitochondria have their own DNA, which gradually accumulates mutations over time. This makes it possible to identify groups of cells that are descended from a single progenitor cell because they will all contain the same mitochondrial mutation. By studying lung tissue from seven individuals, Teixeira et al. were able to identify clusters of related cells and found that, as expected, the size of the clusters increased with age. And by applying a mathematical model across all the cells in the study, it was discovered that whenever one basal progenitor cell committed to a particular fate, another progenitor cell duplicated itself: however, this balancing process happened in a random manner across a large number of cells, and not at the level of individual progenitor cells. Interestingly, it was found random cell division happened among smokers too, but was accelerated. This leads to clusters of identical cells forming more quickly in smokers than in non-smokers. In addition to providing further insights into the origins of lung cancer, the statistical methods developed by Teixeira et al. could be used to analyse the behaviour of many other types of stem or progenitor cells. DOI: http://dx.doi.org/10.7554/eLife.00966.002