Digestive Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health , Bethesda, Maryland.
Laboratory of Biological Modeling, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health , Bethesda, Maryland.
Am J Physiol Gastrointest Liver Physiol. 2019 Jan 1;316(1):G64-G74. doi: 10.1152/ajpgi.00242.2018. Epub 2018 Oct 25.
The normal intestinal epithelium is continuously regenerated at a rapid rate from actively cycling Lgr5-expressing intestinal stem cells (ISCs) that reside at the crypt base. Recent mathematical modeling based on several lineage-tracing studies in mice shows that the symmetric cell division-dominant neutral drift model fits well with the observed in vivo growth of ISC clones and suggests that symmetric divisions are central to ISC homeostasis. However, other studies suggest a critical role for asymmetric cell division in the maintenance of ISC homeostasis in vivo. Here, we show that the stochastic branching and Moran process models with both a symmetric and asymmetric division mode not only simulate the stochastic growth of the ISC clone in silico but also closely fit the in vivo stem cell dynamics observed in lineage-tracing studies. In addition, the proposed model with highest probability for asymmetric division is more consistent with in vivo observations reported here and by others. Our in vivo studies of mitotic spindle orientations and lineage-traced progeny pairs indicate that asymmetric cell division is a dominant mode used by ISCs under normal homeostasis. Therefore, we propose the asymmetric cell division-dominant neutral drift model for normal ISC homeostasis. NEW & NOTEWORTHY The prevailing mathematical model suggests that intestinal stem cells (ISCs) divide symmetrically. The present study provides evidence that asymmetric cell division is the major contributor to ISC maintenance and thus proposes an asymmetric cell division-dominant neutral drift model. Consistent with this model, in vivo studies of mitotic spindle orientation and lineage-traced progeny pairs indicate that asymmetric cell division is the dominant mode used by ISCs under normal homeostasis.
正常的肠道上皮组织以快速的速度从活跃循环的表达 Lgr5 的肠干细胞（ISCs）中不断再生，这些 ISCs 位于隐窝底部。最近的数学模型基于几项在小鼠中的谱系追踪研究表明，对称细胞分裂主导的中性漂移模型与 ISC 克隆在体内观察到的生长非常吻合，并表明对称分裂对 ISC 稳态至关重要。然而，其他研究表明，不对称细胞分裂在体内 ISC 稳态的维持中起着关键作用。在这里，我们表明，具有对称和不对称分裂模式的随机分支和 Moran 过程模型不仅可以模拟 ISC 克隆的随机生长，而且还可以很好地拟合在谱系追踪研究中观察到的体内干细胞动力学。此外，具有最高不对称分裂概率的拟议模型与这里和其他人报告的体内观察结果更一致。我们对有丝分裂纺锤体取向和谱系追踪后代对的体内研究表明，不对称细胞分裂是 ISC 在正常稳态下使用的主要模式。因此，我们提出了不对称细胞分裂主导的中性漂移模型来维持正常的 ISC 稳态。新观点和重要性目前占主导地位的数学模型表明，肠干细胞（ISCs）进行对称分裂。本研究提供的证据表明，不对称细胞分裂是 ISC 维持的主要贡献者，因此提出了一个不对称细胞分裂主导的中性漂移模型。与该模型一致，对有丝分裂纺锤体取向和谱系追踪后代对的体内研究表明，不对称细胞分裂是 ISC 在正常稳态下使用的主要模式。
