Engineering Multicellular Tissue Structure, Function, and Vascularization

工程多细胞组织结构、功能和血管化

基本信息

批准号：
9305084
负责人：
SANGEETA N. BHATIA
金额：
$ 74.26万
依托单位：
BOSTON UNIVERSITY (CHARLES RIVER CAMPUS)
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-06-15 至 2019-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9305084
关键词：
3-Dimensional Acute Address Animal Model Animals Architecture Artificial Liver Biocompatible Materials Biological Models Blood Blood Vessels Cartilage Cell Communication Cell physiology Cells Communication Communities Complex Dependence Development Disease Endothelial Cells Engineering Engraftment Goals Hepatectomy Hepatic Tissue Hepatocyte Homo Human Human Engineering Hydrogels Hypoxia Implant In Vitro Life Liver Liver Failure Liver Regeneration Mediating Metabolic Methods Natural regeneration Nutrient Organ Organ Transplantation Oxygen Paracrine Communication Patients Pattern Perfusion Peritoneal Physiological Play Population Positioning Attribute Process Regenerative Medicine Regenerative response Regulation Research Personnel Role Signal Transduction Skin Solid Source Stimulus Stream Stromal Cells Structure Technology Testing Tissue Engineering Tissue Survival Tissues Transplantation Tyrosinemias Vascular Endothelial Cell Vascular blood supply Vascularization Vision bioprinting cell type chronic liver disease defined contribution engineering design implantation improved improved functioning in vivo liver development liver injury mouse model network architecture novel paracrine public health relevance regenerative response shear stress success tool

项目摘要

DESCRIPTION: The goal of this project is to define multicellular interactions in engineered hepatic tissue that will enable its engraftment and expansion in a living host. In vivo, cell-to-cel 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. Specifically in liver, such interactions appear to be critical for tissue function and regeneration. Unfortunately, few tools currently exist to manipulate multicellular spatial organization; thus little is known about the true impact of tissue architecture to tissue function. During the past 4 years of this collaborative project, the investigators have shown that biomaterials can be used to support the transplantation and peritoneal engraftment of human engineered artificial livers composed of randomly- organized human hepatocytes, endothelial cells and stromal cells. Then, by using novel microtechnology tools to control the organization of these cell types within a 3D context, the team has shown that architecture impacts both the differentiated state of the hepatocyte and the function of the transplanted graft. In addition, the investigators have developed bioprinting tools to build vascular networks in these 3D hydrogels and demonstrated that these improve the survival of co-embedded hepatocytes as well as methods to prevacularize hepatic tissues and thereby accelerate the peritoneal engraftment. In these model systems, we observe that there is a reciprocal interaction via paracrine signals- that is endothelial cells impact hepatocyte function and conversely that hepatocytes impact the endothelial network. Interestingly, many of the paracrine signals are interrelated with perfusion of the network as they are regulated either by shear stress, hypoxia or both. In the current application, the investigators seek to define the spatial dependence on paracrine signaling and perfusion within engineered livers that would efficiently allow them to engraft and expand upon stimulation. The specific aims of this competitive renewal are: (1) To define the role of 3D positioning on paracrine signaling between hepatocytes and endothelial cells in vitro and in vivo, (2) To understand the role of network perfusion on cell function in 3D constructs in vitro and in vivo, and (3) To assess the functional role of network architecture and perfusion on graft expansion in vivo. This project will lead to an integrated understanding of the role of multicellulr organization and cell-cell communication in stabilizing hepatic tissue vascularization and function, and provide new tools and strategies to the broader community to engineer complex multicellular tissues.

描述：该项目的目标是定义工程肝组织中的多细胞相互作用，使其能够在活体宿主中植入和扩增。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的标志。生命，并被认为在天然组织的建立中发挥着关键作用特别是在肝脏中，这种相互作用似乎对组织功能和再生至关重要，但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。在这个合作项目的过去四年中，研究人员已经证明，生物材料可用于支持由随机组织的人类肝细胞、内皮细胞和基质细胞组成的人类工程人工肝脏的移植和腹膜植入，然后通过使用新型材料。通过微技术工具在 3D 背景下控制这些细胞类型的组织，该团队已证明结构会影响肝细胞的分化状态和移植物的功能。研究人员开发了生物打印工具来在这些 3D 水凝胶中构建血管网络，并证明这些工具可以提高共嵌入肝细胞的存活率，以及使肝组织预空化的方法，从而加速腹膜植入。通过旁分泌信号的相互作用，即内皮细胞影响肝细胞功能，反之肝细胞影响内皮网络。旁分泌信号与网络的灌注相互关联，因为它们受到剪切应力、缺氧或两者的调节。在当前的应用中，研究人员试图定义工程肝脏内旁分泌信号和灌注的空间依赖性，从而有效地允许它们植入。并扩展这种竞争性更新的具体目标是：(1) 定义 3D 定位对体外和体内肝细胞和内皮细胞之间的旁分泌信号传导的作用，(2)了解网络灌注对体外和体内 3D 构建体中细胞功能的作用，以及 (3) 评估网络结构和灌注对体内移植物扩张的功能作用。多细胞组织和细胞间通讯在稳定肝组织血管化和功能中的作用，并为更广泛的社区提供新的工具和策略来设计复杂的多细胞组织。