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，但目前对于患有口干症的患者仅是理论上的安慰剂。在以细胞为基础的治疗功能障碍性唾液腺的方法能够进入临床竞技场之前，仍然有几个关键的障碍必须解决。这些包括鉴定合适的供体细胞，促进植入的技术，以及评估结果的直接功能测定。我们建议使用小鼠中可用于追踪细胞谱系和细胞类型的强大且定义明确的遗传工具来解决这些问题。结合可调水凝胶支架，我们将使用已知的唾液腺祖细胞，以确定其在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 相反的环境：再生萎缩的腺体和受损的辐射腺体。目的是确定水凝胶的使用是否可以促进移植祖细胞的体内分化。为了解决移植的细胞是否可以产生唾液，我们建议产生一个表达标记分泌蛋白的小鼠模型。由于该工具识别了分泌物的细胞来源，因此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化研究奠定基础，以将该技术推向临床应用。 公共卫生相关性：该应用结合了小鼠遗传学的工具和生物材料工程的最新进展，提出了两个问题：1）分离的祖细胞群能否用于重建受损唾液腺中的功能性分泌结构？2)将祖细胞引入功能失调的腺体是否诱导内源性修复和/或分泌？在这些关键问题得到解决之前，人类唾液腺的细胞替代疗法不可能取得进展.该项目的成功完成可能为后续的转化研究奠定基础，将开发的技术应用于临床。

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.