Cell Based Regeneration of Salivary Glands

描述(申请人提供)：成体干细胞或祖细胞用于修复受辐射损伤的唾液腺的潜在效用很高，但目前只是一种理论上的解决方案，适用于口干症患者。在以细胞为基础的唾液腺功能障碍治疗进入临床舞台之前，仍有几个关键障碍必须解决。这些包括识别合适的供体细胞，促进植入的技术，以及评估结果的直接功能分析。我们建议使用在小鼠身上可用的强大且定义明确的遗传工具来跟踪细胞谱系和细胞类型，以解决这些问题。结合可调节的水凝胶支架，我们将使用已知的唾液腺前体细胞来确定它们在体外和体内分化所需的环境和细胞信号。这种水凝胶将被用来将细胞移植成两个 相反的环境：再生萎缩的腺体和受损的受辐射的腺体。目的是确定水凝胶的使用是否可以促进移植的祖细胞在体内的分化。为了确定移植细胞是否可以产生唾液，我们建议建立一个表达标记分泌蛋白的小鼠模型。因为这个工具确定分泌物的细胞来源，所以它也可能被证明是评估刺激受损唾液腺内源性再生的方法的关键模型。该项目的成功完成将为后续的转译研究奠定基础，使该技术进入临床应用。

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.