Developmental Mechanisms in Progenitor Cell Therapy of Heart and Blood Disorders

心脏和血液疾病的祖细胞治疗的发育机制

• 批准号: 7674303
• 负责人: Jonathan M. Slack
• 金额: $ 3.78万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-02-01 至 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7674303
• 关键词: Acute; Address; Adult; Allografting; Animal Disease Models; Animal Experimentation; Animal Model; Animals; Biological; Blood; Blood Vessels; Cardiac; Cell Line; Cell Lineage; Cell Therapy; Cells; Cessation of life; Coronary; Development; Developmental Biology; Embryo; Emerging Technologies; Endothelial Cells; Environment; Event; Family suidae; Generations; Genetic; Goals; Graft Survival; Grant; Heart; Heart Diseases; Hematological Disease; Hematopoietic; Hematopoietic stem cells; Human; Image; Immune; Immunosuppression; Individual; Institutes; Laboratories; Left Ventricular Remodeling; Lymphocyte; Magnetic Resonance; Magnetic Resonance Imaging; Measurement; Megakaryocytes; Methodology; Methods; Minnesota; Modeling; Modification; Molecular Genetics; Monitor; Morbidity - disease rate; Mus; Myocardial; Myocardial Infarction; Natural regeneration; Nature; Organ; Patients; Performance; Physiological; Physiology; Population; Production; Property; Protocols documentation; Regenerative Medicine; Research; Role; Route; Side; Solid; Solutions; Source; Specialist; Staging; Stem cells; Techniques; Technology; Testing; Tissue Grafts; Tissues; Transplantation; Universities; Work; base; control trial; embryonic stem cell; extracellular; graft failure; graft function; human disease; imaging modality; in vivo; in vivo Model; member; mortality; novel; novel therapeutics; overexpression; pre-clinical; preclinical study; progenitor; public health relevance; reconstitution; repaired; skills; spectroscopic imaging; stem cell biology; transcription factor

DESCRIPTION (provided by applicant): The use of cell therapies for heart disease has increased steeply over recent years. Initial results suggest modest positive effects on cardiac function but with limited graft survival. We predict that progress will require a focused approach to understanding of the biological mechanisms. To achieve this goal we have formed a multi-disciplinary consortium of labs at the University of Minnesota that includes specialists in embryonic and iPS cell biology, cardiac development, cardiac physiology, myocardial repair, in vivo imaging and large animal research technology. The research plan includes three synergistic and overlapping projects. The first will better define development of hematopoietic and cardiac progenitor cells from ES and iPS cells, by exposing cells to selected environments to mimic the effects of normal development, and by directing differentiation by the overexpression of specific transcription factors. These studies will clarify the developmental relationship between progenitor cells with common hematopoietic and vasculogenic properties (hemangioblasts) and those with cardiogenic and vasculogenic properties (cardiac progenitors). They will also provide a pipeline of cells, and of relevant developmental biology information, for the other projects. The second project will utilize the unique decellularized heart model available at the University of Minnesota to investigate the mechanisms for cardiac colonization by progenitor cells of different developmental stages. The role of resident cells will be established by comparison of the decellularized model with the perfused heart model. Furthermore, the role of systemic factors will be established by comparing both of these to in vivo models. The third project will build on the results of the first two to establish protocols for the performance of successful immunocompatible grafts. We will use either individual-specific iPS cells to produce the graft, or a tissue graft and hematopoietic graft derived from the same cell source. Grafts may be of cells, recellularized tissue patches, or recellularized entire hearts. The most promising protocols will be tested using a swine model of postinfarction left ventricular remodeling, which is well established at the University. The function of grafts will be monitored using novel magnetic resonance methods which will allow the accurate tracking of cells and measurement of important physiological parameters. Collectively, these strategies will utilize novel models to define the mechanisms that govern the regeneration of heart and blood by progenitor cell populations as a prelude for new cell-based regenerative medicine therapies.

描述（由申请人提供）：近年来，细胞疗法在心脏病中的应用急剧增加。初步结果表明，对心脏功能有适度的积极影响，但移植物存活有限。我们预测，要取得进展，需要采取有针对性的方法来理解生物机制。为了实现这一目标，我们在明尼苏达大学组建了一个多学科实验室联盟，其中包括胚胎和 iPS 细胞生物学、心脏发育、心脏生理学、心肌修复、体内成像和大型动物研究技术方面的专家。 该研究计划包括三个协同和重叠的项目。第一个将通过将细胞暴露于选定的环境以模拟正常发育的效果，并通过特定转录因子的过度表达来指导分化，从而更好地定义来自 ES 和 iPS 细胞的造血和心脏祖细胞的发育。这些研究将阐明具有共同造血和血管生成特性的祖细胞（成血管细胞）与具有心源性和血管生成特性的祖细胞（心脏祖细胞）之间的发育关系。他们还将为其他项目提供一系列细胞和相关的发育生物学信息。第二个项目将利用明尼苏达大学独特的脱细胞心脏模型来研究不同发育阶段的祖细胞在心脏定植的机制。通过比较脱细胞模型与灌注心脏模型，将确定常驻细胞的作用。此外，将通过将这两者与体内模型进行比较来确定全身因素的作用。 第三个项目将在前两个项目的基础上建立成功的免疫相容性移植物的方案。我们将使用个体特异性 iPS 细胞来生产移植物，或者使用来自同一细胞来源的组织移植物和造血移植物。移植物可以是细胞、再细胞化的组织块或再细胞化的整个心脏。最有希望的方案将使用猪梗死后左心室重塑模型进行测试，该模型在大学已建立良好。将使用新颖的磁共振方法监测移植物的功能，这将允许准确跟踪细胞并测量重要的生理参数。总的来说，这些策略将利用新的模型来定义祖细胞群控制心脏和血液再生的机制，作为新的基于细胞的再生医学疗法的前奏。

项目成果

Analysis of endogenous Oct4 activation during induced pluripotent stem cell reprogramming using an inducible Oct4 lineage label.

使用诱导型 Oct4 谱系标签分析诱导多能干细胞重编程过程中的内源性 Oct4 激活。

• 发表时间: 2012-11
• 作者: Greder, Lucas V;Gupta, Sandeep;Li, Shunan;Abedin, Md Joynal;Sajini, Abdulrahim;Segal, Yoav;Slack, Jonathan M W;Dutton, James R
• 通讯作者: Dutton, James R