Stem Cells For Myocardial Repair: A Large Bore Magnet Study

描述(申请人提供)：在有梗死后左室重构的心脏中，导致从代偿状态到心力衰竭转变的机制尚不清楚，但可能与梗死周围存活心肌区域(边缘地带，BZ)的进行性收缩功能障碍有关。我们最近发现，心肌梗死周围的边缘带心肌(BZ)比远区心肌(RZ)具有更严重的生物能量异常特征。有报道称，细胞治疗可改善心肌梗死患者的心脏收缩功能。我们最近建立了一个猪骨髓多能成体祖细胞(SmPC)群体，它可以在&gt；100群体倍增时增殖，并在单细胞水平上分化为具有中胚层、神经外胚层和内胚层系的表型和功能特征的细胞。目前的方案中需要检验的一个中心假设是，SmPC将移植到心肌梗死患者的心脏，分化为心肌细胞、血管内皮细胞和平滑肌细胞，干细胞释放的细胞因子诱导天然心肌细胞的增殖和保存。这些有益的影响将在BZ最为突出。BZ的稳定将反过来限制LV心功能的进行性恶化，并防止过渡到CHF。本项目的具体目的是：1.在猪缺血再灌流模型中确定：a)心肌缺血区(IZ)和BZ的收缩期室壁应力升高、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，以及b)在另外8周的随访期内确定这些异常的进展。目的2.确定SmPC心肌移植到BZ是否能在8周的随访期内限制缺血/再灌注引起的IZ、BZ和整体左心功能的异常；B)研究SmPC的可能机制，包括：i)SmPC向心肌细胞、内皮细胞和平滑肌细胞的转分化，改善BZ的血流和功能；ii)营养效应：SmPC释放细胞因子，使原生心肌细胞免于凋亡并诱导新生血管形成；以及C)经冠脉静脉输注干细胞比其他途径更有效。特异性目的3.检测将部分预分化的心肌细胞和来源于SmPC的内皮细胞混合在一种新型的3D多孔聚乙二醇化生长因子增强的生物材料贴片中是否具有更大的益处，这一点在BZ和IZ显著增加了植入率和心肌细胞再生，并进一步降低了室壁应力。公共卫生相关性：心肌梗死后的左心室重构，包括肥厚和心腔扩张，是为了补偿收缩心肌的丧失。在一段时间后，稳定的肥厚心肌功能障碍会发展，并最终可能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。这项建议将检验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一种新的再生疗法。

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.