Expansion of Post-natal Human Stem Cells For A Pre-Clinical Dystrophy Model

产后人类干细胞的扩增用于临床前营养不良模型

• 批准号: 7305918
• 负责人: BRIDGET M DEASY
• 金额: $ 7.18万
• 依托单位: CHILDREN'S HOSP PITTSBURGH/UPMC HLTH SYS
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-01 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7305918
• 关键词: Aging; Behavior; Biological Assay; Biological Markers; Biology; Canada; Cell Aging; Cell Count; Cell Cycle Checkpoint; Cell Cycle Regulation; Cell Therapy; Cell Transplantation; Cells; Chromosome abnormality; Clinical; Clinical Trials; Condition; Cues; Data; Development; Disease; Dose; Duchenne muscular dystrophy; Dystrophin; Exhibits; Future; Genetic; Goals; Growth; Human; In Vitro; Injection of therapeutic agent; Kinetics; Laboratories; Link; Measures; Modeling; Mus; Muscle; Muscular Dystrophies; Myoblasts; Natural regeneration; Neoplasms; Normal Cell; Numbers; Oncogenic; Outcome; Output; Phenotype; Physiological; Population; Population Characteristics; Pre-Clinical Model; Range; Research Personnel; Risk; SCID Mice; Skeletal Muscle; Staging; Standards of Weights and Measures; Stem cells; Testing; Therapeutic; Time; Transplantation; Umbilical Cord Blood; Umbilical cord structure; United States; Work; base; cancer stem cell; clinical application; clinically relevant; human stem cells; improved; in vivo; insight; mathematical model; member; metaplastic cell transformation; muscle regeneration; pre-clinical; prevent; research study; self-renewal; senescence; stem cell therapy

DESCRIPTION (provided by applicant): The development of stem cell therapy for numerous diseases is the goal of researchers working in a wide range of biomedical fields. As progress toward understanding the basic biology of stem cells continues to be made, it is important to maintain a focus on therapeutic applications of these cells by pursuing preclinical models. Members of our laboratory have identified a mouse muscle-derived stem cell population that exhibits an enhanced ability to regenerate skeletal muscle in a muscular dystrophy model. Transplantation of this cell population into the skeletal muscle of mice results in significantly more efficient regeneration (in terms of number of regenerating dystrophin positive myofibers within dystrophic muscle) than does myoblast transplantation therapy, which has been the focus of human clinical trials in both the United States and Canada. We hypothesize that the isolation and transplantation of more potent stem cells such as human muscle-derived stem cells (huMDSCs) or human cord blood stem cells will improve the outcome of cell therapy for muscular dystrophy. We propose here to use a preclinical model to test our ability both to expand human muscle-derived cell populations to achieve therapeutic cell doses (of quality stem cells) and to regenerate skeletal muscle. The primary goals of the cell therapy approach are 1) to generate clinically relevant numbers of (quality or robust) huMDSCs, 2) to maintain their stem cell phenotype, and 3) to prevent their in vitro transformation/ understand their limits. Together these things will increase the quantity of the robust stem cells by maintaining their potent phenotype. In Specific Aim 1 of this proposal, we will expand huMDSC and cord blood stem cell populations to identify the proliferative limits, measure expansion kinetics, and predict clinical expansion time. In Specific Aim 2, we will evaluate the expanded populations for any indication of transformation associated with in vitro aging. We will test for continued self-renewal by assaying molecular markers and multipotency. Most importantly, we will examine the cells for chromosomal aberrations, loss of cell cycle controls, and senescence. We will perform in vivo experiments to test for continued regeneration efficiency and neoplastic growth. These aims will establish standard tests by which to assess any stem cell population in a preclinical setting and will provide basic insight into the possible link between stem cells and cancer stem cells.

描述（由申请人提供）： 开发针对多种疾病的干细胞疗法是广泛生物医学领域研究人员的目标。随着对干细胞基础生物学的了解不断取得进展，通过追求临床前模型来保持对这些细胞的治疗应用的关注非常重要。我们实验室的成员已经鉴定出一种小鼠肌肉来源的干细胞群，该干细胞群在肌营养不良模型中表现出增强的骨骼肌再生能力。将这种细胞群移植到小鼠骨骼肌中，与成肌细胞移植疗法相比，再生效率显着提高（就营养不良肌肉内再生肌营养不良蛋白阳性肌纤维的数量而言），成肌细胞移植疗法一直是美国和加拿大人体临床试验的焦点。我们假设，分离和移植更有效的干细胞，例如人肌肉源性干细胞（huMDSC）或人脐带血干细胞，将改善肌营养不良症细胞疗法的效果。我们在此建议使用临床前模型来测试我们扩大人类肌肉来源的细胞群以达到治疗细胞剂量（优质干细胞）和再生骨骼肌的能力。细胞治疗方法的主要目标是 1) 产生临床相关数量的（优质或稳健的）huMDSC，2) 维持其干细胞表型，3) 防止其体外转化/了解其局限性。这些因素共同作用，将通过维持干细胞的有效表型来增加其数量。在该提案的具体目标 1 中，我们将扩展 huMDSC 和脐带血干细胞群，以确定增殖极限、测量扩展动力学并预测临床扩展时间。在具体目标 2 中，我们将评估扩大的群体是否存在与体外衰老相关的任何转化迹象。我们将通过分析分子标记和多能性来测试持续的自我更新。最重要的是，我们将检查细胞的染色体畸变、细胞周期控制丧失和衰老。我们将进行体内实验来测试持续的再生效率和肿瘤生长。这些目标将建立标准测试，用于评估临床前环境中的任何干细胞群，并将提供对干细胞和癌症干细胞之间可能联系的基本见解。