Gladstone Institute of Cardiovascular Disease, Gladstone Institutes, San Francisco, CA 94158, USA; UC Berkeley-UC San Francisco Graduate Program in Bioengineering, University of California, San Francisco, San Francisco, CA 94158, USA.
Gladstone Institute of Cardiovascular Disease, Gladstone Institutes, San Francisco, CA 94158, USA; Developmental and Stem Cell Biology Ph.D. Program, University of California, San Francisco, San Francisco, CA 94158, USA.
Dev Cell. 2023 Aug 21;58(16):1477-1488.e5. doi: 10.1016/j.devcel.2023.05.019. Epub 2023 Jun 23.
Biological patterning events that occur early in development establish proper tissue morphogenesis. Identifying the mechanisms that guide these patterning events is necessary in order to understand the molecular drivers of development and disease and to build tissues in vitro. In this study, we use an in vitro model of gastrulation to study the role of tight junctions and apical/basolateral polarity in modulating bone morphogenic protein-4 (BMP4) signaling and gastrulation-associated patterning in colonies of human pluripotent stem cells (hPSCs). Disrupting tight junctions via knockdown (KD) of the scaffolding tight junction protein-1 (TJP1, also known as ZO1) allows BMP4 to robustly and ubiquitously activate pSMAD1/5 signaling over time, resulting in loss of the patterning phenotype and marked differentiation bias of pluripotent stem cells to primordial germ cell-like cells (PGCLCs). These findings give important insights into how signaling events are regulated and lead to spatial emergence of diverse cell types in vitro.
生物发生模式事件在早期发育中发生，建立了适当的组织形态发生。为了了解发育和疾病的分子驱动因素，并在体外构建组织，有必要确定指导这些发生模式事件的机制。在这项研究中，我们使用了一个体外原肠胚形成模型，研究了紧密连接和顶/基底极性在调节骨形态发生蛋白-4（BMP4）信号和原肠胚形成相关模式在人多能干细胞（hPSC）集落中的作用。通过敲低（KD）支架紧密连接蛋白-1（TJP1，也称为 ZO1）来破坏紧密连接，使 BMP4 能够随时间强烈和普遍地激活 pSMAD1/5 信号，导致模式表型丧失，多能干细胞明显偏向原始生殖细胞样细胞（PGCLCs）分化。这些发现为了解信号事件如何被调节以及如何导致不同类型的细胞在体外空间出现提供了重要的见解。
