Myocardial regeneration in ischemic cardiomyopathy

描述（由申请人提供）：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治疗策略正在研究中，最近，一些优雅的研究表明，在梗死周围（Ml后几天），自体干细胞移植可显著再生心肌组织。我们最近的研究表明，干细胞归巢分子基质细胞衍生因子-1 （SDF-1）在Ml后会短暂表达，并且在Ml后几个月，通过传递表达SDF-1的工程化细胞，在心肌组织中重新建立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，而无需产生新的心肌细胞（Lancet 362:697- 703,2003）。这些观察结果使我们假设急性Ml和缺血性心肌病心肌再生的可行策略是干细胞归巢到心肌组织的信号的过表达或重建。间充质干细胞（MSCs）在Ml发生后的数天内能够修复受损的心肌，并且被认为比造血干细胞更容易分化为心肌细胞，但它们不表达CXCR4。由于MSCs在骨髓损伤的实验模型中已被证明具有动员作用，并且MSC在梗死周围期对受损心肌具有归巢作用，因此必须存在其他归巢和动员因素。我们假设，为了优化心肌梗死后或充血性心力衰竭患者心肌功能的恢复，我们需要重建HSC和MSC归巢。本提案的总体目标是测试在缺血性心肌病模型中表达干细胞归巢因子用于心肌再生的策略（目的1），确定导致骨髓来源的MSCs归巢的分子触发器（目的2），并确定MSCs中CXCR4的工程表达是否导致SDF-1响应的归巢和细胞在体内的生存优势（目的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).