Engineering the Organizer

设计组织者

• 批准号: 10317741
• 负责人: LANCE A. DAVIDSON
• 金额: $ 22.59万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-15 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10317741
• 关键词: 3-Dimensional; Adult; Amphibia; Anterior; Automobile Driving; Beds; Biological; Biological Assay; Biological Models; Biomedical Research; Biophysics; Cell Density; Cell Differentiation process; Cells; Cellular biology; Centrifugation; Clinic; Clinical Research; Complex; Coupled; Development; Disease; Dorsal; Embryo; Embryonic Development; Embryonic Organizers; Engineering; Ethics; Exposure to; Fibroblast Growth Factor; Future; Gastrula; Genes; Geometry; Goals; Growth Factor; Human; Human Development; Human body; Left; Manuals; Maps; Mechanics; Methods; Modeling; Modernization; Morphogenesis; Morphology; Movement; Natural regeneration; Nobel Prize; Nodal; Organ; Organogenesis; Organoids; Outcome; Pathway interactions; Pattern; Planet Earth; Positioning Attribute; Process; Protocols documentation; Publishing; Rana; Recombinant Growth Factor; Regenerative Medicine; Shapes; Signal Transduction; Site; Sorting - Cell Movement; Source; Specific qualifier value; Speed; Spemann' s Organizer; Structure; System; Techniques; Technology; Testing; Thinness; Tissue Engineering; Tissues; Translating; Undifferentiated; Work; Xenopus; Xenopus laevis; base; bioprinting; blastomere structure; cell behavior; cell type; clinically relevant; density; design; embryo tissue; experience; experimental study; exposure pathway; human embryonic stem cell; human tissue; induced pluripotent stem cell; innovation; magnetic field; mechanical properties; new technology; novel; programs; prototype; scaffold; self assembly; stem cell model; synthetic construct; three dimensional structure; tool; translation to humans; tumor progression

Project Summary: Regeneration and development operate on the sub-millimeter scale, using evolved design principles to drive self-assembly of replacement and new organs. Our goal with this project is to follow the principle of 'the organizer', where a small group of cells are microsurgically grafted into a naive host tissues to pattern and induce organ primordia from the naive tissue. To achieve this we first identify methods to produce stable laminar sheets of naive tissue (i.e. stable host tissues), and to develop novel tools to assemble these laminar sheets, (i.e. in place of manual microsurgical grafts) to enable formation of planar polarized 3D structures. The principles that propel modern tissue engineering are based on classic embryological studies of morphogenesis in organoids. These classic studies relied on amphibian models where specified cells could be isolated from embryos, formed into aggregates, and differentiated into distinctive tissues. Following programs of sorting and engulfment, and differentiation, cells self-assemble planar, polarized laminar sheets with distinct polarity, e.g. anterior-to-posterior, to form tissues consisting of multiple cell types at high cell density. It is now widely recognized that similar, conserved programs of self-assembly shape human tissues during embryogenesis, regeneration, and cancer progression. However, current efforts to engineer complex 3D structures suffer from an inability to reproducibly and reliably generate organized multi-laminar tissues of multiple cell types at high cell density. To date, no tissue engineering approach is capable of recreating multi-laminar polarized 3D structures analogous to those that form at even the earliest stages in the embryo. Using our experience with and expertise in embryonically assembled tissues, we leverage principles of the organizer, and engineer stable multi-laminar tissues with planar polarity. Based on our published methods for shaping 3D embryonic tissues into laminar sheets, we will to expose the cellular that stabilize those sheets and to develop assembly methods to produce planar polarized tissues. Rapid translation to human biomedical research and tissue are made possible by leveraging the speed and accessibility of the amphibian embryonic model to test and translate key findings to human embryonic stem cell models of the organizer. We envision that the long term outcome of this project will transform efforts to engineer and manufacture tissues that can be sourced from human cell types and iPSCs for a wide range of clinical and research applications.

项目摘要： 使用进化的设计原理以次数量表进行再生和开发 驱动自我组装的替换和新器官。我们在这个项目上的目标是遵循 “组织者”，其中一小组细胞被微骨移植到幼稚的宿主组织中，以进行模式和 从幼稚组织诱导器官原始。为此，我们首先确定生产稳定的方法 幼稚组织（即稳定的宿主组织）的层状片，并开发出新的工具来组装这些层流 板，（即代替手动显微外科移植物），以形成平面极化3D结构。这 推动现代组织工程的原理基于形态发生的经典胚胎学研究 在器官中。这些经典研究取决于两栖动物模型，其中可以从中隔离特定的细胞 胚胎形成骨料，并分化为独特的组织。遵循分类程序和 吞噬和分化，细胞自组装平面，极性层状片段具有独特的极性，例如 前到后者，形成由高细胞密度下多种细胞类型组成的组织。现在广泛 认识到，在胚胎发生过程中，类似的，保守的自我组装程序塑造了人体组织， 再生和癌症进展。但是，目前为设计复杂3D结构的努力遭受了 无法重复可靠地生成高于多种细胞类型的有组织的多层组织 细胞密度。迄今为止，没有组织工程方法能够重新创建多层极化3D 结构类似于胚胎中最早的阶段形成的结构。利用我们的经验 和胚胎组装的组织方面的专业知识，我们利用组织者的原理和工程师稳定 具有平面极性的多层组织。根据我们发表的塑造3D胚胎组织的方法 进入层状片，我们将揭露稳定这些床单并开发组装方法的细胞 产生平面偏振组织。快速翻译为人类生物医学研究和组织 通过利用两栖动物胚胎模型的速度和可及性来测试和翻译密钥 组织者人类胚胎干细胞模型的发现。我们设想这是长期的结果 项目将把努力转变为可以从人类细胞类型中采购的组织和制造组织 以及用于广泛的临床和研究应用的IPSC。