Tissue Patterning in living skin and organ ex

活体皮肤和器官中的组织图案

• 批准号: 10249265
• 负责人: Cheng-Ming Chuong
• 金额: $ 52.01万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-21 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10249265
• 关键词: 3-Dimensional; Adult; Architecture; Back; Biochemical; Biological Assay; Biomechanics; Biophysical Process; Biophysics; Blood Vessels; Calcium Channel; Cell Polarity; Cells; Chemicals; Chick Embryo; Competence; Complex; Coupling; Cutaneous Muscle; Dermal; Dermis; Development; Diffuse; Diffusion; Embryo; Engineered skin; Epigenetic Process; Epithelial; Event; Experimental Models; Extracellular Matrix; Feathers; Fibroblast Growth Factor; Fluorescence Resonance Energy Transfer; Funding; Future; Gap Junctions; Generations; Genes; Hair; Hair follicle structure; Image; Knowledge; Lead; Learning; Link; MMP14 gene; Maps; Matrix Metalloproteinases; Mechanics; Molecular; Morphogenesis; Morphology; Mus; Muscle; Natural regeneration; Nerve; Newborn Infant; Organ; Organoids; Pathogenesis; Pathway interactions; Pattern; Pattern Formation; Periodicity; Peripheral; Physiological; Play; Primordium; Process; Progress Reports; Property; Publications; Regenerative Medicine; Role; Second Messenger Systems; Signal Transduction; Skin; Smooth Muscle Myocytes; Stretching; Structure; Tenascin; Time; Tissue Engineering; Tissues; Work; appendage; base; cell motility; in vivo; inhibitor/antagonist; mechanical force; member; morphogens; movie; next generation sequencing; novel; physical property; planar cell polarity; reconstitution; regenerative; skin morphogenesis; skin regeneration; stem cells; tongue papilla; transcriptome sequencing; wound healing

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.

我们的长期目标是研究建立复杂皮肤结构的组织原则 最佳的皮肤功能所需的。我们一直使用发育中的皮肤作为实验模型， 它们独特的模式，我们用它们作为读数，以及它们对实验的可访问性。过去我们 已经采取了一种分析方法来研究通过改变表达水平来破坏组织模式， 不同的可扩散形态发生素。我们和其他人最近的工作启发了我们， 这些过程在组织形成中也起着不可或缺的作用，这些作用还没有得到充分的认识。我们现在 探索这一新奇理解的后果。在这里，我们提出了一个普遍的假设， 通过整合分子信号传导和生物物理事件发生模式化。新表达的分子 导致细胞及其周围基质的物理性质发生变化，引起不平衡 推动生物物理过程进入下一阶段。机械力-化学偶联导致新的分子 表达等等，导致了复杂的建筑。我们将评估三个关键 形态发生事件首先，周期性的图案化过程，将皮肤从一个形态发生 场到多个皮肤附属物单位。我们建议有多层次的控制。组织力学可能 促进图灵模式，并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来调节图灵模式的结果。第二，编队 的干细胞为基础的皮肤附件毛囊在每个单位。羽芽边缘为平面细胞 极性，腱生蛋白C和MMP 14-FRET活性，驱动芽缘上皮内陷到 真皮干细胞和真皮乳头的命运图将使用单细胞RNA测序生成， 谱系追踪，并将结果与毛囊的关键相似性进行比较。第三，适应性 附属结构如血管、神经、真皮肌肉等在背部整合的图案 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 探索这些原则。真皮细胞命运在此过程中的能力、特异性和可塑性 将使用SMA机械传感器在活体外植体中进行表观遗传学分析。通过探索组织的作用 在皮肤的组织图案化过程中，我们可以获得对自我的更全面的理解， 组织皮肤发育和再生的过程。这些知识将具有重大意义。 未来的再生医学应用。