Creating a Localized Pool of iPSCs In Vivo

在体内创建本地化 iPSC 池

• 批准号: 9266778
• 负责人: Gregory M. Cooper
• 金额: $ 7.76万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-01 至 2020-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9266778
• 关键词: Acute; Address; Adipocytes; Alginates; Autopsy; Body Weight decreased; Bone Regeneration; Calvaria; Cause of Death; Cell Separation; Cell Survival; Cell Therapy; Cells; Chronic Disease; Clinical; Clinical Trials; Collagen; Cytomegalovirus; DNA; Data; Defect; Degenerative Disorder; Deterioration; Development; Documentation; Effectiveness; Elements; Encapsulated; Engraftment; Environment; Foundations; Gene Delivery; Generations; Goals; Growth Factor; Histopathology; Immune; Immunohistochemistry; Injury; Liposomes; Methods; MicroRNAs; Modeling; Monitor; Mus; Neurons; Oils; Organ; Organ failure; Palpable; Population; Porifera; Pre-Clinical Model; Route; Site; Somatic Cell; Staining method; Stains; Stem cells; Technology; Testing; Therapeutic; Time; Tissue Model; Tissues; Transfection; Transplantation; Tumorigenicity; United States; Vascularization; Work; base; bone; cell preparation; cell type; clinical translation; craniofacial repair; design; disability; embryonic stem cell; functional restoration; gene therapy; immunogenic; immunogenicity; improved; in vivo; induced pluripotent stem cell; interest; plasmid DNA; pluripotency; public health relevance; regenerative therapy; sonoporation; stem cell biology; stem cell therapy; tissue repair; transcription factor; transdifferentiation; transgene expression; tumor; vector

 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.

 描述：随着时间的推移，慢性和退行性疾病会导致器官或组织退化，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，并已广泛用于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）的产生将规避这些限制。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中体内生成 iPSC。在这项研究中，我们将开发一种有效的体内细胞重编程方法，结合使用用于细胞重编程的微RNA簇miR302/367和用于基因传递的小环DNA。将讨论三个关键因素：1）体内重编程的效率（目标 I），2）体内生成的 iPSC 的多能状态（目标 II），以及 3）与重编程相关的脱靶效应的记录（目标 III）。我们相信体内生成 iPSC 是传统干细胞疗法的可行替代方案。开发一种有效的组织特异性体内重编程方法为设计具有广泛应用的再生疗法奠定了必要的基础。