Pin Carmen, Parker Aimee, Gunning A Patrick, Ohta Yuki, Johnson Ian T, Carding Simon R, Sato Toshiro
Gut Health and Food Safety Research Programme, Institute of Food Research, Norwich, NR4 7UA, UK.
Integr Biol (Camb). 2015 Feb;7(2):213-28. doi: 10.1039/c4ib00236a.
Intestinal crypt fission is a homeostatic phenomenon, observable in healthy adult mucosa, but which also plays a pathological role as the main mode of growth of some intestinal polyps. Building on our previous individual based model for the small intestinal crypt and on in vitro cultured intestinal organoids, we here model crypt fission as a budding process based on fluid mechanics at the individual cell level and extrapolated predictions for growth of the intestinal epithelium. Budding was always observed in regions of organoids with abundant Paneth cells. Our data support a model in which buds are biomechanically initiated by single stem cells surrounded by Paneth cells which exhibit greater resistance to viscoelastic deformation, a hypothesis supported by atomic force measurements of single cells. Time intervals between consecutive budding events, as simulated by the model and observed in vitro, were 2.84 and 2.62 days, respectively. Predicted cell dynamics was unaffected within the original crypt which retained its full capability of providing cells to the epithelium throughout fission. Mitotic pressure in simulated primary crypts forced upward migration of buds, which simultaneously grew into new protruding crypts at a rate equal to 1.03 days(-1) in simulations and 0.99 days(-1) in cultured organoids. Simulated crypts reached their final size in 4.6 days, and required 6.2 days to migrate to the top of the primary crypt. The growth of the secondary crypt is independent of its migration along the original crypt. Assuming unrestricted crypt fission and multiple budding events, a maximal growth rate of the intestinal epithelium of 0.10 days(-1) is predicted and thus approximately 22 days are required for a 10-fold increase of polyp size. These predictions are in agreement with the time reported to develop macroscopic adenomas in mice after loss of Apc in intestinal stem cells.
肠隐窝裂变是一种稳态现象，在健康成年黏膜中可见，但它作为一些肠息肉的主要生长方式也发挥着病理作用。基于我们之前建立的小肠隐窝个体模型以及体外培养的肠类器官，我们在此将隐窝裂变建模为基于单个细胞水平流体力学的出芽过程，并推断出肠上皮生长的预测结果。出芽现象总是在潘氏细胞丰富的类器官区域观察到。我们的数据支持这样一种模型，即芽是由被潘氏细胞包围的单个干细胞通过生物力学方式引发的，潘氏细胞对粘弹性变形表现出更大的抵抗力，这一假设得到了单细胞原子力测量的支持。模型模拟和体外观察到的连续出芽事件之间的时间间隔分别为2.84天和2.62天。预测的细胞动力学在原始隐窝内不受影响，原始隐窝在整个裂变过程中保留了为上皮提供细胞的全部能力。模拟的初级隐窝中的有丝分裂压力迫使芽向上迁移，芽同时以模拟中等于1.03天⁻¹、培养的类器官中等于0.99天⁻¹的速率生长成新的突出隐窝。模拟的隐窝在4.6天内达到其最终大小，并需要6.2天迁移到初级隐窝的顶部。次级隐窝的生长与其沿原始隐窝的迁移无关。假设隐窝不受限制地裂变和多次出芽事件，预测肠上皮的最大生长速率为0.10天⁻¹，因此息肉大小增加10倍大约需要22天。这些预测与报道的肠道干细胞中Apc缺失后小鼠发生宏观腺瘤的时间一致。
