Investigating the formation of spatial and directional patterns in the mammalian epidermis

研究哺乳动物表皮空间和方向模式的形成

• 批准号: 9789003
• 负责人: Liliya Leybova
• 金额: $ 4.5万
• 依托单位: PRINCETON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9789003
• 关键词: Ablation; Adhesions; Architecture; Biophysics; Cadherins; Cell Adhesion Molecules; Cell Lineage; Cell-Cell Adhesion; Cells; Complex; Cues; Development; Dimensions; Embryo; Epidermis; Epithelial; Epithelial Cells; Epithelium; Event; Gene Expression; Gene Expression Profiling; Generations; Genetic Transcription; Goals; Growth; Hair; Hair follicle structure; Image; Individual; Intercellular Junctions; Lasers; Maps; Mesenchymal; Methods; Morphogenesis; Morphology; Mosaicism; Movement; Myosin ATPase; Organ; Patients; Pattern; Population; Positioning Attribute; Property; Radial; Regenerative Medicine; Reproducibility; Rotation; Signal Transduction; Skin; Specific qualifier value; Stem cells; Structure; System; Testing; Tissue Engineering; Tissues; Tube; Tubular formation; WNT Signaling Pathway; beta catenin; cell behavior; cell fate specification; cell motility; cell type; differential expression; driving force; imaging genetics; novel; planar cell polarity; polarized cell; progenitor; programs; response; transcription factor

Project Summary The development of epithelial organs involves a complex interplay between epithelial- mesenchymal interactions, cell fate induction, proliferation, and tissue polarity. In epithelial organs, intercellular signaling and mesenchymal interactions specify the spatial patterns of tubes, branches, and other specialized cell types. How these events are coordinated to generate organs with precise and reproducible patterns, dimensions, and sizes remains poorly understood. With recent advancements that allow patient-specific stem cells to be differentiated into organs in a dish, how these forms arise has become increasingly important to resolve. The goal of this proposal is to decipher how intercellular signaling, cell fate specification, and tissue polarity coordinate morphogenesis of developing the skin epithelium. The mammalian skin, which is decorated with spatially patterned, globally aligned hair follicles is an excellent system to explore how polarized architecture is established in multicellular structures. Recently we discovered an unexpected and novel collective cell behavior that directs morphological and cell fate asymmetry in developing hair placodes. The polarization of initially circular hair placodes is driven by dramatic cell rearrangements coordinated in a counter-rotational pattern of cell flows. To generate the pattern of cell flow, spatial patterning of radial cell fates cooperates with planar cell polarity to direct polarized cell neighbor exchanges through myosin-dependent junction disassembly. Using a combination of live imaging, genetic mosaics, biophysical manipulations and transcriptional profiling, the following proposal will test the hypothesis that differences in motility, contractile forces on intercellular junctions and cell-cell adhesion between inner and outer placode cells drive counter-rotational cell movements during placode polarization. Successful completion of these aims will provide an integrated view of how cell signaling, cell fate specification, polarity and adhesion cooperate to generate a novel mode of tissue morphogenesis. We anticipate that counter-rotating cell rearrangements may be in fact be widespread in epithelial organs, polarizing a wide array of branched and tubular structures. Thus, our findings are likely having a broad impact on the fields of regenerative medicine and tissue engineering.

项目摘要 上皮性器官的发育涉及上皮性-内脏之间复杂的相互作用。 间充质相互作用，细胞命运诱导，增殖，和组织极性。在上皮性 器官、细胞间信号和间充质相互作用规定了 管、分支和其他专门化细胞类型。如何协调这些活动以 制造出具有精确和可重复的图案、尺寸和大小的器官仍然很差 明白了。随着最近的进展，患者特定的干细胞可以分化 进入盘子里的器官，这些形式是如何出现的，越来越需要解决。这个 这项提议的目标是破译细胞间信号、细胞命运规范和组织 极性协调皮肤上皮发育的形态发生。哺乳动物的皮肤， 它由空间图案的、全球排列的毛囊装饰，是一个极好的系统 探索极化结构是如何在多细胞结构中建立的。最近我们 发现了一种意想不到的、新颖的集体细胞行为，它指导着形态和细胞 头发安慰剂发育过程中命运的不对称性。最初呈圆形的毛发胎头的偏振为 由戏剧性的细胞重排驱动，在细胞流动的反旋转模式中协调。 为了产生细胞流动的图案，放射状细胞命运的空间图案与平面 细胞极性通过肌球蛋白依赖的连接引导极化的细胞邻居交换 拆卸。使用活体成像、基因镶嵌、生物物理操作的组合 和转录特征分析，下面的建议将检验以下假设： 细胞间连接上的运动性、收缩力以及细胞与细胞之间的黏附 在胎盘极化过程中，外层胎盘细胞驱动反旋转的细胞运动。 这些目标的成功完成将提供细胞信号、细胞 命运规范、极性和粘附性共同作用产生一种新的组织模式 形态发生。我们预计，反向旋转的细胞重排实际上可能是 广泛分布于上皮性器官，极化广泛的分支和管状结构。 因此，我们的发现可能会对再生医学和 组织工程学。