Amplification of Cardiosphere-Derived Cell Therapy

描述（由申请人提供）：常住成人心脏干细胞的发现引起了人们对利用心脏内源性再生潜力开发基于细胞的治疗方法的兴趣，以逆转心肌细胞损失并改善缺血性心脏病患者的心室功能。从心肌活检中分离的心球源性细胞（cdc）是最近发现的成体干细胞来源，通过直接分化为心肌细胞和刺激内源性心肌细胞增殖来促进心脏再生和增强收缩功能。在这些初步结果的基础上，人们的注意力已经转向确定扩大cdc介导的心脏修复的策略。一种新的方法是利用出生后早期心脏细胞的高度增殖表型，这可能为具有优越再生潜力的cdc的衍生提供来源。因此，本提案的目的是验证中心假设，即在出生后早期心脏发育过程中，来自年轻心脏的cdc在促进心脏修复方面优于来自老年心脏的cdc。为了验证这一假设，将在大型慢性缺血性心脏病动物模型中比较年轻心源性cdc （y - cdc）和老年心源性cdc （a - cdc）冠状动脉内给药后的疗效。具体而言，Aim 1将检查每个细胞群的能力，以引起猪心肌收缩功能和灌注的改善，这是由慢性冠状动脉狭窄引起的冬眠心肌。在Aim 2中，我们将评估y - cdc和a - cdc增加心肌细胞核密度、刺激心肌细胞增殖、调动内源性祖细胞以及向心肌细胞和血管分化的能力。为了开始探索这些细胞群之间假设差异的潜在机制，Y-CDC和A-CDC端粒酶活性和端粒长度将在Aim 3中进行评估。确定年轻心脏来源的CDC优越的再生特性将导致未来的工作，研究这种功能益处背后的细胞和分子机制，以及对老年心脏病患者的同种异体年轻供体来源的CDC管理的转化研究。此外，细胞重编程方法的进步（例如，诱导多能干细胞）可能最终使研究人员能够在老年人细胞中重现年轻的CDC表型，最终导致新策略的发展，以优化心脏修复并防止冠状动脉疾病患者左心室功能障碍进展为临床心力衰竭。

DESCRIPTION (provided by applicant): The discovery of resident adult cardiac stem cells has generated interest in exploiting the heart's endogenous regenerative potential for the development of cell-based therapies to reverse myocyte loss and improve ventricular function in patients with ischemic heart disease. Cardiosphere-derived cells (CDCs) isolated from myocardial biopsies are a recently identified source of adult stem cells that promote cardiac regeneration and enhance contractile function through both direct differentiation into cardiac myocytes and by stimulating endogenous myocyte proliferation. To build on these initial results, attention has been directed towards identifying strategies to amplify CDC-mediated cardiac repair. One novel approach is to capitalize on the highly proliferative phenotype of cardiac cells in the heart during early postnatal development, which may provide a source for the derivation of CDCs with superior regenerative potential. Accordingly, the objective of this proposal is to test the central hypothesis that CDCs derived from the young heart during early postnatal cardiac development are superior to CDCs from the aged adult heart in promoting cardiac repair. To test this hypothesis, the efficacy of young heart-derived CDCs (Y-CDCs) and aged heart-derived CDCs (A-CDCs) will be compared following intracoronary administration in a large animal model of chronic ischemic heart disease. Specifically, Aim 1 will examine the capacity of each cell population to elicit improvements in myocardial contractile function and perfusion in swine with hibernating myocardium resulting from a chronic coronary stenosis. In Aim 2, the ability of Y-CDCs and A-CDCs to increase myocyte nuclear density, stimulate myocyte proliferation, mobilize endogenous progenitor cells, and differentiate into cardiac myocytes and blood vessels will be evaluated. To initiate exploration of potential mechanisms underlying the hypothesized differences between these cell populations, Y-CDC and A-CDC telomerase activity and telomere length will be assessed in Aim 3. Identification of superior regenerative properties of young heart-derived CDCs would lead to future work examining the cellular and molecular mechanisms underlying this functional benefit, as well as translational investigation of allogeneic young donor-derived CDC administration to older adults with heart disease. Moreover, advancements in methods of cell re-programming (e.g., induced pluripotent stem cells) may eventually allow researchers to recapitulate the youthful CDC phenotype in cells from older adults, ultimately leading to the development of novel strategies to optimize cardiac repair and prevent the progression of left ventricular dysfunction to clinical heart failure in patients wth coronary artery disease.