Factors Responsible for Cardiac Preservation Conferred by Adult Marrow Stem Cells

成体骨髓干细胞赋予心脏保护的因素

基本信息

批准号：
7367354
负责人：
JEFFREY L SPEES
金额：
$ 33.61万
依托单位：
UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-01-10 至 2012-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7367354
关键词：
Acute Adult Allogenic Animals Apoptotic Area Autologous Bone Marrow Bone Marrow Cells Bone Marrow Stem Cell Buffers Cardiac Cardiac Myocytes Cell Separation Cell Therapy Cell surface Cells Clinical Condition Conditioned Culture Media Country Data Dose Effectiveness Engraftment Environment Epitopes Experimental Designs Fibroblasts Growth Heart Hematopoietic Hematopoietic Stem Cell Transplantation Hematopoietic stem cells Human Hypoxia Immune Immunocompetent Immunodeficient Mouse Infarction Inhibition of Apoptosis Injection of therapeutic agent Injury Intramuscular Intramuscular Injections Intravenous Left ventricular structure Magnetism Marrow Mesenchymal Stem Cells Methods Mitotic Molecular Profiling Mononuclear Mouse Strains Mus Myocardial Infarction Myocardium NGFR Protein Natural regeneration Nature Necrosis Oxygen Patients Phenotype Population Procedures Property Proteins Proteomics Recovery Relative (related person)Reporting Route STAT3 gene Saline Serum Serum-Free Culture Media Site Sorting - Cell Movement Source Stem cells Tail Testing Time Tissues Undifferentiated Veins Week base cell injury cell preparation compare effectiveness day design heart preservation injured paracrine progenitor repaired research study stem transcription factor transcriptional coactivator p75

项目摘要

DESCRIPTION (provided by applicant): The adult bone marrow non-hematopoietic stem cells known as mesenchymal stem cells (MSCs) promote functional cardiac recovery in animals with myocardial infarction (MI). In several countries these cells have been administered to patients with MI with reported beneficial effects. Despite the efficacy of MSC administration, most studies have shown that few of the cells engraft long-term and that only a portion of the surviving cells appear to differentiate to a mature cardiac phenotype. In animals injection of concentrated conditioned medium into cardiac muscle appears to have effects similar to those of direct injection of cells, implying that secreted factors from the cells comprise the principle basis for the benefits. Our preliminary data demonstrate that non-hematopoietic human bone marrow stem cells can exert cardiac protective and reparative effects when delivered intravenously (IV) to animals with MI. Furthermore, we show that serum-free medium conditioned by mixed MSCs or by standardized MSCs isolated by magnetic sorting for the p75 low affinity nerve growth factor receptor (p75LNGFR; p75MSCs) can support the growth and survival of adult cardiac stem/progenitor cells through activation of the transcription factor STAT3. Because MSCs are prepared from a heterogeneous mixture of adherent cells, it is desirable to have a standardized isolation procedure for a population of progenitor cells that predictively imparts cardiac protection and/or repair. We have recently isolated sub-populations of non-hematopoietic stem cells from the total mononuclear cells of bone marrow by specific cell surface epitopes. They may be particularly well-suited for cardiac preservation based on their expression profiles of secreted proteins. Comparing the effectiveness of one of these sub-populations (p75MSCs) to mixed adherent MSCs, we will determine whether intravenous or intramuscular administration of non-autologous stem cells can be used to provide paracrine-based cardiac cell therapy. We will identify the factors secreted by the stem cells that are effective and determine whether the mechanism of action is sparing of existing cardiomyocytes by inhibition of apoptosis or necrosis or augmenting the proliferation and survival of endogenous cardiac stem cells. SPECIFIC AIMS 1. To identify a cardioprotective sub-population of human bone marrow stem cells and determine the growth conditions and timing of administration necessary to rescue cardiac function after MI in immunodeficient mice. 2. To determine the ability of strain-mismatched murine bone marrow stem cells delivered intravenously or intramuscularly to promote cardiac protection or recovery after MI in immunocompetent mice. 3. To identify the specific factors secreted by the stem cells that preserve cardiac function.

描述（由申请人提供）：被称为间充质干细胞（MSC）的成体骨髓非造血干细胞可促进患有心肌梗塞（MI）的动物的功能性心脏恢复。在一些国家，这些细胞已被用于心肌梗死患者，据报道有有益效果。尽管 MSC 给药有效，但大多数研究表明，很少有细胞能够长期移植，并且只有一部分存活细胞似乎分化为成熟的心脏表型。在动物中，将浓缩条件培养基注射到心肌中似乎具有与直接注射细胞相似的效果，这意味着细胞分泌的因子构成了这些益处的主要基础。我们的初步数据表明，非造血人类骨髓干细胞通过静脉注射（IV）给患有心肌梗死的动物时可以发挥心脏保护和修复作用。此外，我们还发现，通过混合 MSC 或通过磁力分选分离的 p75 低亲和力神经生长因子受体（p75LNGFR；p75MSC）的标准化 MSC 调节的无血清培养基可以通过激活支持成体心脏干/祖细胞的生长和存活转录因子 STAT3。由于 MSC 是由贴壁细胞的异质混合物制备的，因此需要对祖细胞群有标准化的分离程序，以预测性地赋予心脏保护和/或修复作用。我们最近通过特定的细胞表面表位从骨髓的总单核细胞中分离出了非造血干细胞的亚群。基于其分泌蛋白的表达谱，它们可能特别适合心脏保存。通过比较这些亚群之一 (p75MSC) 与混合贴壁 MSC 的有效性，我们将确定是否可以使用静脉内或肌肉内施用非自体干细胞来提供基于旁分泌的心脏细胞治疗。我们将鉴定干细胞分泌的有效因子，并确定其作用机制是否是通过抑制细胞凋亡或坏死或增强内源性心脏干细胞的增殖和存活来保护现有的心肌细胞。具体目标 1. 鉴定人类骨髓干细胞的心脏保护亚群，并确定免疫缺陷小鼠心肌梗死后挽救心脏功能所需的生长条件和给药时机。 2. 确定静脉或肌肉注射品系不匹配的小鼠骨髓干细胞促进免疫功能正常小鼠心肌梗死后心脏保护或恢复的能力。 3. 鉴定干细胞分泌的维持心脏功能的特定因子。