Mammalian early development comprises the proliferation, differentiation, and self-assembly of the embryonic cells. The classic experiment undertaken by Townes and Holtfreter demonstrated the ability of dissociated embryonic cells to sort and self-organize spontaneously into the original tissue patterns. Here, we further explored the principles and mechanisms underlying the phenomenon of spontaneous tissue organization by studying aggregation and sorting of mouse embryonic stem (ES) cells with differential adhesive affinity in culture. As observed previously, in aggregates of wild-type and E-cadherin-deficient ES cells, the cell assemblies exhibited an initial sorting pattern showing wild-type cells engulfed by less adhesive E-cadherin-deficient ES cells, which fits the pattern predicted by the differential adhesive hypothesis proposed by Malcom Steinberg. However, in further study of more mature cell aggregates, the initial sorting pattern reversed, with the highly adhesive wild-type ES cells forming an outer shell enveloping the less adhesive E-cadherin-deficient cells, contradicting Steinberg’s sorting principle. The outer wild-type cells of the more mature aggregates did not differentiate into endoderm, which is known to be able to sort to the exterior from previous studies. In contrast to the naive aggregates, the mature aggregates presented polarized, highly adhesive cells at the outer layer. The surface polarity was observed as an actin cap contiguously spanning across the apical surface of multiple adjacent cells, though independent of the formation of tight junctions. Our experimental findings suggest that the force of differential adhesive affinity can be overcome by even subtle polarity generated from strong bilateral ligation of highly adhesive cells in determining cell sorting patterns.

中文翻译：

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具有不同粘附亲和力的胚胎干细胞聚集体中细胞分选模式的动态转换

哺乳动物早期发育包括胚胎细胞的增殖、分化和自组装。Townes 和 Holtfreter 进行的经典实验证明了分离的胚胎细胞能够自发地分类和自组织成原始组织模式。在这里，我们通过研究具有不同粘附亲和力的小鼠胚胎干（ES）细胞在培养中的聚集和分选，进一步探索了自发组织组织现象的原理和机制。如前所述，在野生型和 E-cadherin 缺陷型 ES 细胞的聚集体中，细胞组装体表现出初始分选模式，显示野生型细胞被粘附性较低的 E-cadherin 缺陷型 ES 细胞吞噬，这符合 Malcom Steinberg 提出的差异粘合剂假设所预测的模式。然而，在对更成熟的细胞聚集体的进一步研究中，最初的分选模式发生了逆转，高度粘附的野生型 ES 细胞形成了一个外壳，包裹着粘附性较低的 E-钙粘蛋白缺陷细胞，这与 Steinberg 的分选原理相矛盾。更成熟的聚集体的外部野生型细胞没有分化成内胚层，已知内胚层能够从先前的研究中分选到外部。与幼稚的聚集体相比，成熟的聚集体在外层呈现出极化的、高度粘附的细胞。表面极性被观察为连续跨越多个相邻细胞的顶端表面的肌动蛋白帽，尽管与紧密连接的形成无关。