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


哺乳动物的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具有自发分类和自组织成原始组织模式的能力。在这里，我们通过研究培养物中具有不同粘附亲和力的小鼠胚胎干（ES）细胞的聚集和分选，进一步探讨了自发组织组织现象的原理和机制。正如之前所观察到的，在野生型和 E-钙粘蛋白缺陷型 ES 细胞的聚集体中，细胞集合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-钙粘蛋白缺陷型 ES 细胞吞噬，这符合预测的模式马尔科姆·斯坦伯格提出的微分粘合剂假说。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，高粘附性的野生型 ES 细胞形成了外壳，包围了粘附性较低的 E-钙粘蛋白缺陷细胞，这与 Steinberg 的分选原理相矛盾。更成熟聚集体的外部野生型细胞不会分化为内胚层，根据先前的研究已知内胚层能够分选到外部。与幼稚聚集体相反，成熟聚集体在外层呈现极化的、高度粘附的细胞。表面极性被观察为肌动蛋白帽连续跨越多个相邻细胞的顶端表面，尽管与紧密连接的形成无关。 我们的实验结果表明，在确定细胞分选模式时，通过高度粘附细胞的强力双边结扎产生的细微极性，可以克服不同的粘附亲和力。