Stem Cells For Myocardial Repair: A Large Bore Magnet Study

用于心肌修复的干细胞：大口径磁铁研究

• 批准号: 8076911
• 负责人: Jianyi Zhang
• 金额: $ 47.85万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-16 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8076911
• 关键词: Acute myocardial infarction; Adult; Affect; Animals; Anterior Descending Coronary Artery; Apoptosis; Attenuated; Binding; Biocompatible Materials; Bioenergetics; Biological Preservation; Bone Marrow; Cardiac; Cardiac Myocytes; Cell Transplants; Cell physiology; Cells; Characteristics; Chemicals; Clinical; Congestive Heart Failure; Data; Deterioration; Development; Distal; Endoderm; Endothelial Cells; Endothelium; Engraftment; Family suidae; Fibrin; Functional disorder; Growth Factor; Health; Heart; Heart Hypertrophy; Heart failure; Hepatocyte; Hypertrophy; Infarction; Injury; Ischemia; Label; Lead; Left; Left Ventricular Dysfunction; Left Ventricular Function; Left Ventricular Remodeling; Left ventricular structure; Ligation; Literature; Magnetic Resonance; Magnetic Resonance Imaging; Measures; Mechanics; Mesenchymal Stem Cells; Mesoderm; Methods; Modeling; Muscle Cells; Myocardial; Myocardial Infarction; Myocardial dysfunction; Myocardium; Natural regeneration; Neuroectoderm; Oxidative Phosphorylation; Oxygen; Patients; Performance; Perfusion; Phosphocreatine; Population; Proliferating; Radial; Radioactive; Reperfusion Therapy; Reporting; Route; Severities; Shapes; Site; Smooth Muscle; Smooth Muscle Myocytes; Stem cell transplant; Stem cells; Stress; Structure of left gastric vein; Surface; Testing; Time; Transplantation; Ventricular; base; blood flow measurement; cytokine; deoxymyoglobin; follow-up; functional improvement; hemodynamics; improved; inorganic phosphate; intravenous drip; mouse model; neovascularization; novel; paracrine; prevent; progenitor; repaired; research study; response; spectroscopic imaging; transdifferentiation

DESCRIPTION (provided by applicant): In hearts with postinfarction LV remodeling, the mechanisms that contribute to the transition from the compensated state to heart failure remain unclear, but may be related to progressive contractile dysfunction of the region of viable myocardium that surrounds the infarct (border zone, BZ). We have recently found that the border zone region of myocardium (BZ) surrounding an infarct has much more severe abnormal bioenergetic characteristics than remote zone myocardium (RZ). It has been reported that cellular therapy improves LV contractile function in hearts with myocardial infarction. We have recently established a population of multipotent adult progenitor cells from swine bone marrow (sMPC) that can proliferate for >100 population doublings, and differentiate at the single cell level into cells with phenotypic and functional characteristics of mesoderm, neuroectoderm, and endoderm lineages. A central hypothesis to be tested in the current proposal is that the sMPC will engraft into hearts with myocardial infarcts, differentiate into cardiomyocytes, endothelium and smooth muscle, and cytokine released from the stem cells induce proliferation and preservation of native myocytes. These beneficial effects will be most prominent in the BZ. BZ stabilization will in turn, limit progressive deterioration of LV chamber function and prevent transition to CHF. The specific aims of this project are: SPECIFIC AIM 1.To determine in a pig ischemia and reperfusion model: a) the relationships between elevated systolic LV wall stress, bioenergetic abnormalities and contractile dysfunction in the myocardial ischemic zone (IZ) and BZ and the severity of global LV dysfunction, and b) determine the progression of these abnormalities over an additional 8 week follow-up period. SPECIFIC AIM 2. To determine whether: A) myocardial transplantation of sMPC into BZ will limit ischemia/reperfusion induced abnormalities in IZ, BZ and global LV function over an 8 week followup period; B) examine possible mechanisms of sMPC benefits including: i) transdifferentiation of sMPC to cardiomyocytes, endothelial and, smooth muscle cells that improve BZ perfusion and function, ii ) a trophic effect: sMPC release cytokines that spare native cardiomyocytes from apoptosis and induce neovascularization; and C) intra-coronary vein infusion of stem cells is more effective that the other routes of delivery. SPECIFIC AIM 3. To examine whether a mixture of partially pre-differentiated cardiomyocytes and endothelium derived from sMPC delivered within a novel 3D porous PEGylated growth factor enhanced biomaterial patch, will have greater beneficial effects, which are evidenced by significantly increase in the engraftment rate and myocyte regeneration, and further reduction the LV wall stress in BZ and IZ. PUBLIC HEALTH RELEVANCE: Post-infarction left ventricular remodeling including hypertrophy and chamber dilation occurs to compensate for loss of contractile myocardium. After a period stable hypertrophy myocardial dysfunction can develop and may ultimately lead to overt congestive heart failure (CHF) that is a most significant clinical problem. This proposal will examine whether a PEGylated fibrin patch based stem cell transplantation can provide a new regeneration therapy for heart failure patients.

描述（由申请人提供）：在梗死后LV重构的心脏中，导致从代偿状态转变为心力衰竭的机制尚不清楚，但可能与梗死周围存活心肌区域（边界区，BZ）的进行性收缩功能障碍有关。我们最近发现，心肌梗死周围的边界区（BZ）比远区心肌（RZ）具有更严重的异常生物能量特征。已有报道细胞疗法可改善心肌梗死患者的左室收缩功能。我们最近建立了一群来自猪骨髓的多能成体祖细胞（sMPC），其可以增殖>100个群体倍增时间，并在单细胞水平分化成具有中胚层、神经外胚层和内胚层谱系的表型和功能特征的细胞。在当前提议中待测试的中心假设是sMPC将移植到具有心肌梗死的心脏中，分化成心肌细胞、内皮细胞和平滑肌，并且从干细胞释放的细胞因子诱导天然肌细胞的增殖和保存。这些有益的影响将在BZ中最为突出。BZ稳定反过来将限制LV腔室功能的进行性恶化并防止转变为CHF。本研究的具体目的是：1.在猪缺血再灌注模型中确定：a）心肌缺血区（IZ）和BZ的收缩期LV壁应力升高、生物能量异常和收缩功能障碍与整体LV功能障碍的严重程度之间的关系，和B）确定这些异常在额外的8周随访期内的进展。具体目标2.确定是否：A）将sMPC心肌移植到BZ中将在8周的随访期内限制缺血/再灌注诱导的IZ、BZ和整体LV功能的异常; B）检查sMPC益处的可能机制，包括：i）sMPC转分化为改善BZ灌注和功能的心肌细胞、内皮细胞和平滑肌细胞，ii）营养效应：sMPC释放使天然心肌细胞免于凋亡并诱导新血管形成的细胞因子;和C）干细胞的冠状静脉内输注比其他递送途径更有效。具体目标3.为了检查在新型3D多孔PEG化生长因子增强生物材料贴片内递送的源自sMPC的部分预分化心肌细胞和内皮的混合物是否具有更大的有益效果，其通过植入率和肌细胞再生的显著增加以及BZ和IZ中LV壁应力的进一步降低来证明。公共卫生关系：心肌梗死后左室重构包括肥厚和腔室扩张，以补偿收缩心肌的损失。一段时间后，稳定的心肌肥厚可能发展为心肌功能障碍，并可能最终导致明显的充血性心力衰竭（CHF），这是一个最重要的临床问题。该提案将研究基于聚乙二醇化纤维蛋白贴片的干细胞移植是否可以为心力衰竭患者提供新的再生治疗。