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: 7626617
• 负责人: SANGEETA N. BHATIA
• 金额: $ 73.31万
• 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 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7626617
• 关键词: Address; Affect; Animals; Architecture; Automobile Driving; Beds; Blood Vessels; Cadherins; Capillary Endothelial Cell; Cartilage; Case Study; Cell Communication; 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; 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; public health relevance; success; tool; two-dimensional

DESCRIPTION (provided by applicant): 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 interactions in supporting hepatocyte function, and interactions between parenchymal and vascular compartments in driving angiogenesis. Interestingly, there appear to be relevant pair wise 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. Public Health Relevance Statement: This project will develop tools to organize multiple cell types within an engineered liver construct to maximize tissue function and integration with the patient's blood supply. As such, these studies will address several major hurdles towards the engineering of tissues for treating diseases that are otherwise only cured by whole organ transplantation.

描述（由申请人提供）： 该项目重点研究细胞的空间组织和由此产生的细胞间相互作用如何调节组织工程结构内稳定组织功能的发育和维持。在体内，通过近分泌和旁分泌信号介导的细胞间通讯和合作是多细胞生命的标志，并且被认为在天然组织功能的建立中发挥着关键作用。因为组织内细胞的空间组织决定了哪些细胞类型之间存在哪些并置，所以这种架构最终可以决定组织工程构建最终会失败还是成功。 不幸的是，目前很少有工具可以操纵多细胞空间组织。因此，人们对组织结构对组织功能的真正影响知之甚少。该项目的长期目标是开发这样的细胞模式工具，利用它们研究多细胞组织在调节组织功能中的作用，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，但研究人员将重点作为血管化工程肝脏开发的案例研究。研究人员最近开发了几种多细胞模式工具，并用它们证明了肝细胞-基质细胞相互作用在支持肝细胞功能中的重要性，以及实质和血管区室之间的相互作用在驱动血管生成中的重要性。有趣的是，在这种情况下，几种细胞类型之间似乎存在相关的成对相互作用，并且涉及可溶性旁分泌信号和通过钙粘蛋白接合的直接效应的组合。从这些早期研究中可以明显看出，需要进行仔细的机制研究来解卷积并了解这些多重相互作用将如何促进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功能性组织。建议需要进行多方面的体外和体内努力来开发必要的工具和研究来实现这些目标。具体目标 1 将是使用几种新颖的二维图案工具研究肝细胞、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血管生成功能中的作用。具体目标 2 将是研究三维结构中的细胞组织如何影响组织功能。具体目标 3 是探索多细胞组织在体内环境中调节组织整合和血管化的作用。除了生成图案化多细胞类型构建体的新方法外，研究人员还将开发用于非侵入性监测组织血管化的纳米颗粒。该项目将导致对多细胞组织和细胞间通讯在稳定组织功能中的作用的综合理解，并提供新的工具和策略来设计复杂的多细胞组织。 公共健康相关性声明：该项目将开发工具，在工程肝脏结构中组织多种细胞类型，以最大限度地提高组织功能并与患者的血液供应整合。因此，这些研究将解决组织工程治疗疾病的几个主要障碍，否则只能通过整个器官移植来治愈。