Adult Stem Cells for Repair Cardiac Damage

描述(由申请人提供)： 最近的报道提出了一种可能性，即使用来自骨髓的成人干细胞可能会为急性和慢性心脏病提供戏剧性的新疗法。然而，要开发一种安全有效的成人干细胞疗法，必须解决一些问题和问题。我们将重点关注来自骨髓的成体干细胞，称为间充质干细胞或骨髓基质细胞(MSCs)。与其他干细胞相比，这种干细胞具有几个优点，即它们可以很容易地从患者身上分离出来进行治疗，它们不是致瘤性的，它们具有多种分化为多种细胞表型的潜力，并且它们已经显示出非凡的能力来定位组织损伤部位和修复损伤。我们首先将彻底描述我们最近鉴定的MSCs的不同亚类，其中显然包括标准培养的MSCs中最早的祖细胞和最具多潜能的细胞。然后，我们将首先在简单的体外与心脏细胞共培养系统中比较用于植入和分化的细胞的标准化准备，然后在大鼠的急性和慢性心脏缺血损伤的体内模型中进行比较。具体目标是：(1)进一步鉴定我们最近从MSCs培养物中分离出的特殊的干细胞亚类，这些干细胞具有异常长的端粒，并且比平行的MSCs样本繁殖更快。我们将验证这一假设，即细胞是RS前细胞，即快速自我更新细胞(RS细胞)的前体，我们以前在标准的MSCs培养中将其确定为早期祖细胞的亚群。(2)采用体外共培养系统，比较RS前体细胞、RS细胞、骨髓间充质干细胞和骨髓单个核细胞通过细胞直接分化和细胞融合修复心肌细胞缺氧损伤的能力。(3)分离和鉴定大鼠骨髓中可能的前RS细胞、RS细胞、mMSCs和单个核细胞，用于体内心肌缺血模型的研究4.(4)检测rMSCs、mMSCs、前RS细胞、RS细胞和大鼠骨髓单个核细胞在急性心肌梗死(缺血-再灌注)和冠状动脉形成(间歇性反复缺血)模型中植入并改善功能和减轻损伤的能力。

DESCRIPTION (provided by applicant): Recent reports have raised the possibility that use of adult stem cells from bone marrow may provide dramatic new therapies for both acute and chronic cardiac diseases. However, to develop a safe and effective therapy with adult stem cells, a number of problems and issues must be resolved. We will focus our attention on the adult stem cells from bone marrow referred to as either mesenchymal stem cells or marrow stromal cells (MSCs). The cells have several advantages over other stem cells in that they can readily be isolated from a patient to be treated, they are not tumorogenic, they are multipotential for differentiation into many cell phenotypes, and they have shown a remarkable ability to home to sites of tissue injury and repair the injury. We will first thoroughly characterize distinct subclasses of MSCs that we have recently identified and that apparently include the earliest progenitors and the most multipotential cells in standard cultures of MSCs. We will then compare standardized preparations of the cells for engraftment and differentiation first in a simple ex vivo co-culture system with cardiac cells, and then in rat in vivo models for acute and chronic ischemic damage to heart. The Specific Aims are: (1) Further characterize the special subclass of stem-like cells that we have recently isolated from cultures of MSCs and that have unusually long telomeres and propagate more rapidly than parallel samples of MSCs. We will test the hypothesis that the cells are pre-RS cells, i.e. precursors of the rapidly self-renewing cells (RS cells) that we previously identified as a sub-population of early progenitors in standard cultures of MSCs. (2) Use an ex vivo co-culture system to compare the ability of the putative pre-RS cells, RS cells, mMSCs, and marrow mononuclear cells, to repair hypoxic damage to cardiac cells either through direct differentiation of the cells or through cell fusion. (3) Isolate and characterize putative pre-RS ceils, RS cells, mMSCs, and mononuclear cells from rat bone marrow for testing in in vivo models of cardiac ischemia in Specific Aim 4. (4) Determine the ability of rMSCs, mMSCs, pre-RS, RS, and unfractionated mononuclear cells from rat marrow to engraft into and produce functional improvement and reduce damage in rat models of acute myocardial infarction (ischemia-reperfusion) and coronary arteriogenesis (intermittent repetitive ischemia).