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.

项目概要： 再生和发展在亚毫米尺度上运作，使用进化的设计原则， 驱动替换器官和新器官的自我组装。我们在这个项目中的目标是遵循以下原则 “组织者”，其中一小群细胞通过显微外科手术移植到幼稚宿主组织中以形成图案， 从幼稚组织诱导器官原基为了实现这一点，我们首先确定方法，以产生稳定的 幼稚组织（即稳定的宿主组织）的层状片材，并开发新的工具来组装这些层状片材。 片（即代替手动显微外科移植物），以能够形成平面偏振3D结构。的 推动现代组织工程的原理是基于形态发生的经典胚胎学研究 在类器官中。这些经典的研究依赖于两栖动物模型，其中特定的细胞可以从 胚，形成聚集体，并分化成独特的组织。以下程序的排序和 吞噬和分化时，细胞自组装成具有不同极性的平面、极化层状片，例如， 从前到后，以形成由高细胞密度的多种细胞类型组成的组织。现在人们普遍 认识到在胚胎发生过程中类似的、保守的自组装程序塑造了人类组织， 再生和癌症进展。然而，目前工程复杂3D结构的努力受到以下问题的影响： 不能在高浓度下可重复地和可靠地产生多种细胞类型的有序多层组织， 细胞密度迄今为止，没有组织工程方法能够重建多层偏振3D 这些结构甚至与胚胎最早期形成的结构类似。利用我们的经验 和胚胎组装组织的专业知识，我们利用组织者的原则， 具有平面极性的多层组织。基于我们发表的3D胚胎组织成形方法 我们将暴露稳定这些薄片的细胞，并开发组装方法。 以产生平面偏振组织。快速转化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访问性来测试和翻译关键 这一研究结果应用于组织者的人类胚胎干细胞模型。我们设想，长期的结果， 该项目将改变工程和制造可来源于人类细胞类型的组织的努力 和iPSC用于广泛的临床和研究应用。