Creating a Localized Pool of iPSCs In Vivo

 产品说明：慢性和退行性疾病导致器官或组织随时间退化，是美国死亡和残疾的主要原因。干细胞具有恢复受损组织功能的能力，并已用于广泛的临床前模型中以促进组织修复。然而，这些疗法的临床转化由于与细胞分离、离体操作和移植相关的问题而变得复杂。体内诱导多能干细胞（iPSC）的产生将克服这些限制。研究表明，组织微环境可以支持体内重编程和转分化，但迄今为止尚未尝试在特定组织环境内体内产生iPSC。在这项研究中，我们将开发一种有效的方法在体内重编程细胞使用的microRNA簇miR 302/367的细胞重编程和微环DNA的基因传递的组合。将解决三个关键因素：1）体内重编程的效率（目标I），2）体内产生的iPSC的多能性状态（目标II），和3）与重编程相关的脱靶效应的记录（目标III）。我们相信体内产生iPSC是传统干细胞疗法的可行替代方案。开发组织特异性体内重编程的有效方法为设计具有广泛应用的再生疗法奠定了必要的基础。

 DESCRIPTION: Chronic and degenerative diseases result in organ or tissue deterioration over time and are the leading cause of death and disability in the United States. Stem cells have the capacity to restore function to damaged tissues and have been used in a wide range of pre-clinical models to promote tissue repair. However, clinical translation of these therapies has been complicated by issues associated with cell isolation, ex vivo manipulation, and transplantation. In vivo generation of induced pluripotent stem cells (iPSCs) would circumvent these limitations. Studies have demonstrated that tissue microenvironments can support in vivo reprogramming and transdifferentiation, but in vivo generation of iPSCs within a specific tissue environment has not been attempted to date. In this study we will develop an efficient method for reprogramming cells in vivo using a combination of the micro RNA cluster miR302/367 for cellular reprogramming and minicircle DNA for gene delivery. Three key factors will be addressed: 1) efficiency of in vivo reprogramming (Aim I), 2) pluripotency state of the in vivo generated iPSCs (Aim II), and 3) documentation of off target effects associated with reprogramming (Aim III). We believe that generating iPSCs in vivo is a viable alternative to traditional stem cell therapies. Developing an efficient method for tissue specific in vivo reprogramming lays the necessary foundation for designing regenerative therapies with a broad range of applications.