Amplification of Cardiosphere-Derived Cell Therapy

描述（由申请人提供）：常驻成体心脏干细胞的发现引起了人们对开发心脏内源性再生潜力的兴趣，以开发基于细胞的疗法来逆转缺血性心脏病患者的肌细胞损失并改善心室功能。从心肌活检中分离的心肌球衍生细胞（CDC）是最近鉴定的成体干细胞的来源，其通过直接分化为心肌细胞和刺激内源性肌细胞增殖来促进心脏再生和增强收缩功能。为了建立在这些初步的结果，注意力已被导向确定策略，以扩大CDC介导的心脏修复。一种新的方法是利用出生后早期发育过程中心脏中心脏细胞的高度增殖表型，这可能为具有上级再生潜力的CDC的衍生提供来源。因此，本提案的目的是检验中心假设，即在出生后早期心脏发育期间来自年轻心脏的CDC在促进心脏修复方面上级来自老年成人心脏的CDC。为了检验这一假设，将在慢性缺血性心脏病的大型动物模型中冠状动脉内给药后比较年轻心脏来源的CDC（Y-CDC）和老年心脏来源的CDC（A-CDC）的功效。具体而言，目标1将检查每种细胞群引起慢性冠状动脉狭窄导致冬眠心肌的猪的心肌收缩功能和灌注改善的能力。在目标2中，将评价Y-CDC和A-CDC增加肌细胞核密度、刺激肌细胞增殖、动员内源性祖细胞以及分化成心肌细胞和血管的能力。为了开始探索这些细胞群之间假设差异的潜在机制，将在目标3中评估Y-CDC和A-CDC端粒酶活性和端粒长度。年轻心脏来源的CDC的上级再生特性的鉴定将导致未来的工作检查这种功能益处的细胞和分子机制，以及同种异体年轻供体来源的CDC给老年心脏病患者的转化研究。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的细胞中重现年轻的CDC表型，最终导致开发新的策略来优化心脏修复并防止患有冠状动脉疾病的患者的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.