Cell Based Regeneration of Salivary Glands

描述（由申请人提供）：成体干细胞或祖细胞用于修复辐射损伤的唾液腺的潜在效用很高，但目前仅是对口干症患者的理论解决方案。在对功能失调的唾液腺进行细胞治疗进入临床领域之前，仍有几个关键的障碍必须解决。这些包括合适的供体细胞的鉴定，促进植入的技术，以及评估结果的直接功能分析。我们建议解决这些问题，使用强大的和定义良好的遗传工具，在小鼠中追踪细胞谱系和细胞类型。结合可调水凝胶支架，我们将使用已知的唾液腺祖细胞来确定其体外和体内分化所需的环境和细胞线索。水凝胶将用于将细胞移植到两个细胞中

DESCRIPTION (provided by applicant): The potential utility of adult stem or progenitor cells for repair of radiation-damaged salivary glands is high, but is currently only a theoretical solutin for patients suffering from xerostomia. There remain several critical obstacles that must be resolved before cell-based therapy for dysfunctional salivary glands can be moved into the clinical arena. These include the identification of appropriate donor cells, the technology for promoting implantation, and direct functional assays to assess the outcomes. We propose to address these issues, using the powerful and well-defined genetic tools available in mice for tracing cell lineages, and cell types. In combination with tunable hydrogel scaffolds, we will use known salivary gland progenitor cells to determine environmental and cellular cues required for their differentiation in vitro and in vivo. The hydrogels will be used to transplant cells into two opposite environments: regenerating atrophic glands, and damaged irradiated glands. The goal is to determine if the use of hydrogels can promote in vivo differentiation of transplanted progenitor cells. To resolve whether the transplanted cells can produce saliva, we propose to generate a mouse model expressing a tagged secretory protein. Because this tool identifies the cellular source of the secretion, it may also prove to be a critical model for evaluating ways to stimulate endogenous regeneration of damaged salivary glands. The successful completion of this project will establish a foundation for subsequent translational research to progress the technology into clinical applications. PUBLIC HEALTH RELEVANCE: This application combines the tools of mouse genetics with recent advances in biomaterial engineering to ask two questions: 1) Can isolated progenitor cell populations be used to reconstitute functional secretory structures in a damaged salivary gland? 2) Does the introduction of progenitor cells into a dysfunctional gland induce endogenous repair and/or secretion? Until these critical questions are resolved, progress toward cell- based replacement therapy in human salivary glands cannot occur. The successful completion of this project may lay the foundation for subsequent translational research to take the developed technology into clinical applications.