Engineering Multicellular Tissue Structure, Function and Vascularization

工程多细胞组织结构、功能和血管化

• 批准号: 8242801
• 负责人: SANGEETA N. BHATIA
• 金额: $ 66.32万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-15 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8242801
• 关键词: Address; Affect; Animals; Architecture; Automobile Driving; Beds; Blood Vessels; Cadherins; Capillary Endothelial Cell; Cartilage; Case Study; Cell Communication; Cell Differentiation process; Cell physiology; Cells; Cellular Structures; Complex; Development; Devices; Disease; Endothelial Cells; Engineering; Fibroblasts; Generic Drugs; Goals; Growth; Hepatocyte; Homo; Hydrogels; Implant; In Vitro; Lead; Life; Liver; Maintenance; Mediating; Methods; Modeling; Mus; Organ; Organ Transplantation; Paracrine Communication; Patients; Pattern; Performance; Pharmacologic Substance; Physiological; Play; Research; Research Personnel; Role; Signal Transduction; Skin; Stromal Cells; Structure; Structure-Activity Relationship; Surface; System; Testing; Time; Tissue Engineering; Tissues; Transplantation; Vascular blood supply; Vascularization; Work; abstracting; angiogenesis; cell growth; cell type; chorioallantoic membrane; design; human tissue; implantation; in vivo; intercellular communication; liver function; meetings; membrane model; migration; nanoparticle; non-invasive monitor; novel; novel strategies; paracrine; success; tool; two-dimensional

Title: Engineering Multicellular Tissue Structure, Function, and Vascularization Abstract This project focuses on how the spatial organization of cells and resultant cell-cell interactions regulate the development and maintenance of stable tissue function within a tissue engineered construct. In vivo, cell-to- cell communication and cooperation mediated through juxtacrine and paracrine signals is a hallmark of multicellular life, and is thought to play a critical role in the establishment of native tissue functions. Because the spatial organization of cells within tissues defines which juxtapositions exist between which cell types, this architecture ultimately can determine whether a tissue engineered construct ultimate will fail or succeed. Unfortunately, few tools currently exist to manipulate multicellular spatial organization; thus little is known about the true impact of tissue architecture to tissue function. The long-term goal of this project is to develop such cellular patterning tools, to use them to investigate the role of multicellular organization in regulating tissue function, and to explore how such organization can be used to enhance the function of engineered tissues. While the tools to be developed can be considered generic, the investigators will focus as a case study on the development of a vascularized engineered liver. The investigators have recently developed several multicellular patterning tools, and used them to demonstrate the importance of both hepatocyte-stromal cell- cell interactions in supporting hepatocyte function, and interactions between parenchymal and vascular compartments in driving angiogenesis. Interestingly, there appear to be relevant pairwise interactions that occur between several cell types in this setting, and involve a combination of soluble paracrine signals and direct effects through cadherin engagement. It is apparent from these early studies that careful mechanistic studies are necessary to deconvolute and understand how these multiple interactions will contribute to the vascularization and differentiated function of the liver construct, so that a rational strategy can be developed to ultimately construct a functional tissue. It is proposed that a multifaceted in vitro and in vivo effort will be required to develop the necessary tools and studies to meet these goals. Specific Aim 1 will be to investigate the role of cell-cell interactions between hepatocytes, fibroblasts, and endothelial cells in regulating liver and angiogenic functions using several novel two-dimensional patterning tools. Specific Aim 2 will be to investigate how the organization of cells in three-dimensional constructs affects tissue function. Specific Aim 3 will be to explore the involvement of multicellular organization in regulating tissue integration and vascularization in an in vivo setting. In addition to novel approaches to generate patterned multi-cell type constructs, the investigators will also develop nanoparticles for non-invasive monitoring of tissue vascularization. This project will lead to an integrated understanding of the role of multicellular organization and cell-cell communication in stabilizing tissue function, and provide new tools and strategies to engineer complex multicellular tissues.

标题：工程多细胞组织结构、功能和血管形成 摘要 这个项目的重点是细胞的空间组织和由此产生的细胞-细胞相互作用如何调节 在组织工程构建中开发和维持稳定的组织功能。在体内，细胞到- 通过旁分泌和旁分泌信号介导的细胞交流和合作是 多细胞生命，并被认为在建立天然组织功能中起着关键作用。因为 组织内细胞的空间组织定义了哪些细胞类型之间存在哪些并列，这 架构最终决定了组织工程构建最终是失败还是成功。 遗憾的是，目前几乎没有工具来操纵多像元空间组织；因此，人们对此知之甚少 组织结构对组织功能的真正影响。这个项目的长期目标是开发这样的 细胞构图工具，用它们来研究多细胞组织在调节组织中的作用 并探索如何利用这种组织来增强工程组织的功能。 虽然要开发的工具可以被认为是通用的，但调查人员将把重点放在 血管化的工程化肝脏的研制。调查人员最近开发出了几个 多细胞构图工具，并用它们来证明肝细胞-基质细胞- 支持肝细胞功能的细胞相互作用以及实质和血管之间的相互作用 推动血管生成的隔室。有趣的是，似乎存在相关的成对互动 在这种情况下，发生在几种细胞类型之间，并涉及可溶性旁分泌信号和 通过钙粘附素参与的直接影响。从这些早期的研究中可以明显看出，细心的机械论 有必要进行研究来了解和了解这些多重相互作用将如何有助于 肝脏结构的血管化和分化功能，从而可以制定合理的策略来 最终构建出一种功能组织。据建议，体外和体内的多方面努力将是 需要开发必要的工具和研究来实现这些目标。具体目标1将是调查 肝细胞、成纤维细胞和内皮细胞之间的细胞间相互作用在调节肝脏和 使用几种新的二维图案化工具的血管生成功能。具体目标2将是调查 三维结构中细胞的组织如何影响组织功能。具体目标3将是 探讨多细胞组织参与调控血管内皮细胞的组织整合和血管生成 活体设置。除了产生图案化多细胞类型结构的新方法外，研究人员还 还将开发用于非侵入性监测组织血管形成的纳米颗粒。这个项目将导致一个 对多细胞组织和细胞间通讯在稳定中的作用的综合理解 组织功能，并为设计复杂的多细胞组织提供新的工具和策略。