Tissue Patterning in living skin and organ ex

我们的长期目标是研究建立复杂皮肤架构的组织原则 是最佳皮肤功能所必需的。我们一直使用发育中的皮肤作为实验模型，因为 它们独特的模式，我们用来作为读数，以及它们对实验的可及性。在过去，我们 已经采取了一种分析的方法来研究通过改变组织模式的表达水平来破坏组织模式 不同的可扩散形态因子。我们和其他人最近的工作告诉我们，生物物理学 工艺在组织图案化中也扮演着不可或缺的角色，而这些角色一直被低估。我们现在 探索这种新奇理解的后果。在这里，我们提出一个普遍的假设，即组织 图案化是通过整合分子信号和生物物理事件发生的。新表达的分子在 细胞会导致细胞及其周围基质的物理性质发生变化，从而导致失衡 这将推动生物物理过程进入下一阶段。机械力-化学耦合导致新的分子 表达等等，导致了复杂建筑的建造。我们将评估三个关键因素 形态发生事件。首先，周期性的图案化过程将皮肤从一种形态转化为 字段设置为多个外观附加单元。我们建议使用多层控件。组织力学可以 促进图灵图案化和帮助芽形成波的传播，而缝隙连接可能会改变 细胞内第二信使的扩散以调节图灵模式的结果。第二，阵型 每个单位的干细胞皮肤附属物毛囊的数量。羽芽边缘呈平面细胞。 极性、Tenascin C和MMP14-FRET活性驱动芽缘上皮内陷到 真皮。干细胞和毛乳头的命运图将使用单细胞RNA测序和 血统追踪，结果将与毛囊的结果进行比较，以寻找关键的相似性。第三，适应性 附属物结构，如血管、神经、真皮肌肉等被整合到背部的图案 以形成一个功能单位。我们将使用真皮肌肉网络的组装作为范例 来探索这些原则。真皮细胞命运在这一过程中的能力、规格和可塑性 将在活的外植体中使用SMA机械传感器进行表观遗传学分析。通过探索组织的作用 力学在皮肤的组织图案化过程中，我们可以对自我有一个更全面的了解 皮肤发育和再生过程中的组织过程。这一知识将具有重要的意义 未来再生医学的应用。

Our long-term objective is to study the organizing principles that establish complex skin architectures required for optimal skin functions. We have been using developing skin as experimental models because of their distinct patterns which we use as a readout and their accessibility to experimentation. In the past, we have taken an analytical approach to study the disruption of tissue patterns by altering expression levels of different diffusible morphogens. Recent work from us and others have enlightened us that biophysical processes also play integral roles in tissue patterning, and these roles have been under appreciated. We now explore the ramifications of this novel understanding. Here we formulate a general hypothesis that tissue patterning occurs by integrating molecular signaling and biophysical events. Newly expressed molecules on cells lead to changes in the physical properties of cells and their surrounding matrix, causing disequilibrium that drives biophysical processes to the next stage. Mechano-chemical coupling leads to new molecular expression and so on, leading to the building of complex architectures. We will evaluate three key morphogenetic events. First, the periodic patterning process that converts the skin from one morphogenetic field to multiple skin appendage units. We suggest there are multi-layered controls. Tissue mechanics may facilitate Turing patterning and help the propagation of the bud forming wave, while gap junctions may alter the diffusion of intra-cellular second messengers to modulate the results of Turing patterns. Second, the formation of stem cell-based skin appendage follicles in each unit. The margin of the feather bud shows planar cell polarity, Tenascin C, and MMP14-FRET activity that drives bud margin epithelium to invaginate into the dermis. Fate maps of stem cells and dermal papillae will be generated using singe cell RNA sequencing and lineage tracing, and the results will be compared with that of hair follicles for key similarities. Third, adaptive patterning in which adnexal structures such as blood vessels, nerves, dermal muscles, etc. are integrated back to the skin to form one functional unit. We will use the assembly of the dermal muscle network as a paradigm to explore these principles. The competence, specification and plasticity of dermal cell fates during this process will be analyzed epigenetically using a SMA mechanosensor in living explants. By exploring the roles of tissue mechanics in during tissue patterning of the skin, we can obtain a more holistic understanding of the self- organizing processes in the development and regeneration of the skin. This knowledge will have significant applications toward regenerative medicine in the future.