Stem Cells For Myocardial Repair: A Large Bore Magnet Study

描述（由申请人提供）：在梗死后左室重构的心脏中，导致从代偿状态过渡到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，梗死周围的边界区心肌（BZ）比远区心肌（RZ）具有更严重的生物能异常特征。有报道称细胞治疗可改善心肌梗死患者左室收缩功能。我们最近从猪骨髓（sMPC）中建立了一个多能成年祖细胞群体，该群体可以增殖100倍，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谱系表型和功能特征的细胞。本研究的一个中心假设是sMPC将植入心肌梗死后的心脏，分化为心肌细胞、内皮细胞和平滑肌细胞，干细胞释放的细胞因子诱导原生心肌细胞增殖和保存。这些有益的影响将在BZ最为突出。BZ稳定将反过来限制左室功能的逐步恶化，并防止过渡到CHF。该项目的具体目标是：在猪缺血再灌注模型中确定：a)心肌缺血区（IZ）和BZ收缩性左室壁应力升高、生物能量异常和收缩功能障碍与整体左室功能障碍严重程度之间的关系；b)在额外的8周随访期间确定这些异常的进展。具体目标2。A)在8周的随访期间，sMPC心肌移植入BZ是否会限制缺血/再灌注引起的IZ、BZ和整体左室功能异常；B)研究sMPC益处的可能机制，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灌注和功能；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；C)冠状静脉输注干细胞比其他输注途径更有效。具体目标3。为了检验部分预分化的心肌细胞和来自sMPC的内皮细胞的混合物在新型3D多孔聚乙二醇化生长因子增强生物材料贴片内传递是否会产生更大的有益效果，这可以通过显著提高移植率和心肌细胞再生来证明，并进一步降低BZ和IZ的左室壁应力。公共卫生相关性：梗死后左心室重构包括肥厚和心室扩张，以补偿收缩心肌的损失。一段时间后，稳定肥厚的心肌功能障碍可发展，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。本研究将探讨聚乙二醇化纤维蛋白贴片干细胞移植能否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.