Myocardial regeneration in ischemic cardiomyopathy

描述(申请人提供)：急性心肌梗死(Ml)仍然是发病率和死亡率的主要原因。涉及自体细胞移植的新的治疗策略正在研究中，最近的一些优雅的研究表明，在梗死周期间(ML后的几天)移植自体干细胞可以显著地再生心肌组织。我们最近发现，干细胞归巢分子基质细胞衍生因子-1(SDF-1)在ML后瞬时表达，并且在ML后数月通过表达SDF-1的工程细胞在心肌组织中重建SDF-1的表达足以诱导造血干细胞(HSC)的干细胞归巢、血管生成和心肌功能的恢复，而不产生新的心肌细胞(Lancet 362：697-703,2003)。这些观察结果使我们假设，急性心肌梗死和缺血性心肌病心肌再生的一个可行策略是过度表达或重新建立干细胞归巢到心肌组织的信号。间充质干细胞(MSCs)在急性心肌梗死后数天内修复受损心肌，被认为比HSCs更有可能分化为心肌细胞，但它们不表达CXCR4。由于骨髓间充质干细胞在实验性的骨髓损伤模型中被证明是动员的，而骨髓间充质干细胞在梗死周围期是受损心肌的归巢和动员因子，因此必须存在其他归巢和动员因子。我们假设，为了优化ML术后或充血性心力衰竭患者的心肌功能恢复，我们需要重建HSC和MSC归巢。这项建议的总体目标是测试在缺血性心肌病模型(目标1)中表达干细胞归巢因子以促进心肌再生的策略，识别导致骨髓来源的MSCs归巢的分子触发因素(目标2)，并确定CXCR4在MSCs中的工程表达是否导致对SDF-1的响应归巢和体内细胞存活优势(目标3)。

DESCRIPTION (provided by applicant): Acute myocardial infarction (Ml) remains a leading cause of morbidity and mortality. Novel therapeutic strategies involving autologous cell transplantation are being studied, and recently, elegant studies have shown significant regeneration of myocardial tissue by transplantation of autologous stem cells during the peri-infarct period (days following Ml). We have recently shown that the stem cell homing molecule stromal-cell derived factor-1 (SDF-1) is transiently expressed following Ml, and that re-establishment of SDF-1 expression in myocardial tissue months after Ml via the delivery of cells engineered to express SDF-1 is sufficient to induce stem cell homing of hematopoietic stem cells (HSC), vasculogenesis and recovery of myocardial function without the generation of new cardiac myocytes (Lancet 362:697-703, 2003). These observations have led us to hypothesize that a viable strategy for myocardial regeneration in acute Ml and ischemic cardiomyopathy is the overexpression or re-establishment of signaling for stem cell homing to myocardial tissue. Mesenchymal stem cells (MSCs) do home to injured myocardium within days of an Ml and are believed to be more likely to differentiate into cardiac myocytes than HSCs, but they do not express CXCR4. Since MSCs have been shown to mobilize in experimental models of bone marrow injury, and MSC do home to injured myocardium in the peri-infarct period other homing and mobilization factors must be present. We hypothesize that in order to optimize recovery of myocardial function following Ml or in patients with congestive heart failure we need to reestablish both HSC and MSC homing. The overall objectives of this proposal are to test strategies for expressing stem cell homing factors for myocardial regeneration in a model of ischemic cardiomyopathy (Aim 1), identify molecular triggers that lead to homing of bone marrow derived MSCs (Aim 2), and determine if engineering expression of CXCR4 in MSCs leads to homing in response to SDF-1 and a cell survival advantage in vivo (Aim 3).