Colon stem cell and crypt dynamics exposed by cell lineage reconstruction.
Colon stem cell and crypt dynamics exposed by cell lineage reconstruction.
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DOI：
10.1371/journal.pgen.1002192
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发表时间：
2011-07
期刊：
影响因子：
4.5
通讯作者：
Shapiro E
中科院分区：
文献类型：
--
作者：
Reizel Y;Chapal-Ilani N;Adar R;Itzkovitz S;Elbaz J;Maruvka YE;Segev E;Shlush LI;Dekel N;Shapiro E
干细胞在体内的动力学通常通过谱系追踪方法来研究。我们的实验室以前开发了一种回顾性的方法，用于从微卫星中积累的体细胞突变重建细胞谱系树。这种方法在这里应用于探索不同方面的干细胞动力学在小鼠结肠不使用干细胞标记。我们首先通过证实先前建立的事实证明了我们研究干细胞方法的可靠性，然后我们解决了悬而未决的问题。我们的研究结果证实，结肠隐窝是单克隆的，并且在整个成年期，单克隆转化的过程在隐窝的维持中起着重要作用。微卫星突变的年龄依赖性积累证实了隐窝干细胞中不存在永生链机制。此外，我们通过显示结肠被分成共享共同祖先的小域，证实了隐窝的物理和谱系接近性之间的正相关性。我们获得了新的数据，表明结肠上皮细胞与造血细胞和其他细胞类型分开聚集，表明结肠由很少的祖细胞组成，并排除了成年期结肠上皮细胞从造血细胞的显著更新。总的来说，我们的研究证明了干细胞动力学研究的细胞谱系重建的可靠性，并进一步解决了结肠干细胞中的开放问题。此外，该方法还可用于研究其他系统中的干细胞动力学。体内干细胞和组织动力学的研究通常通过谱系追踪方法进行，该方法取决于特定标记物的存在和干细胞的可用性。在目前的研究中，我们应用了一种新的方法，从小鼠生命过程中积累的微卫星突变中重建细胞谱系树。我们专注于肠上皮，因为它的干细胞被各种追踪方法深入研究，阐明了它们动力学的许多方面。我们首先证实了我们的方法的可靠性，通过确认三个先前建立的事实：“单克隆转化”的存在，在结肠干细胞中不存在不朽链机制，以及结肠分离成小域，每个域都有一个共同的祖先。我们还回答了一些开放性问题，表明结肠的谱系与其他谱系如造血和胰腺谱系是分开的。总的来说，我们的工作为干细胞动力学的研究提供了一种新的方法，并且可以类似地用于研究其他系统中的干细胞动力学。
Stem cell dynamics in vivo are often being studied by lineage tracing methods. Our laboratory has previously developed a retrospective method for reconstructing cell lineage trees from somatic mutations accumulated in microsatellites. This method was applied here to explore different aspects of stem cell dynamics in the mouse colon without the use of stem cell markers. We first demonstrated the reliability of our method for the study of stem cells by confirming previously established facts, and then we addressed open questions. Our findings confirmed that colon crypts are monoclonal and that, throughout adulthood, the process of monoclonal conversion plays a major role in the maintenance of crypts. The absence of immortal strand mechanism in crypts stem cells was validated by the age-dependent accumulation of microsatellite mutations. In addition, we confirmed the positive correlation between physical and lineage proximity of crypts, by showing that the colon is separated into small domains that share a common ancestor. We gained new data demonstrating that colon epithelium is clustered separately from hematopoietic and other cell types, indicating that the colon is constituted of few progenitors and ruling out significant renewal of colonic epithelium from hematopoietic cells during adulthood. Overall, our study demonstrates the reliability of cell lineage reconstruction for the study of stem cell dynamics, and it further addresses open questions in colon stem cells. In addition, this method can be applied to study stem cell dynamics in other systems. The study of stem cell and tissue dynamics in vivo is often carried out by lineage tracing methods that depend on the presence of specific markers and on the availability of stem cells. In the current study, we applied a novel method for the reconstruction of cell lineage trees from microsatellite mutations accumulated during mouse life. We focused on the intestinal epithelium, since its stem cells were intensively studied by various tracing methods that clarified many aspects of their dynamics. We first showed the reliability of our method by confirming three previously established facts: the existence of “monoclonal conversion,” the absence of an immortal strand mechanism in colon stem cells, and the separation of the colon into small domains each with a common ancestor. We also answered a few open questions, showing that the colon's lineage is separated from other lineages such as the hematopoietic and pancreatic lineages. Overall, our work presents a new approach for the study of stem cell dynamics and can similarly be used for studying stem cell dynamics in other systems.
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