Amplification of Cardiosphere-Derived Cell Therapy

心脏圈衍生细胞疗法的放大

• 批准号: 8457177
• 负责人: Brian Raymond Weil
• 金额: $ 4.92万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT BUFFALO
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8457177
• 关键词: Address; Adult; Age; Allogenic; Animal Model; Anterior Descending Coronary Artery; Attention; Autologous; Biopsy; Blood Vessels; Cardiac; Cardiac Myocytes; Cell Aging; Cell Cycle; Cell Therapy; Cell Transplantation; Cells; Chronic; Clinical; Complex; Coronary Arteriosclerosis; Coronary Stenosis; Derivation procedure; Development; Elderly; Engraftment; Exhibits; Family suidae; Functional disorder; Future; Heart; Heart Diseases; Heart failure; Injection of therapeutic agent; Investigation; Laboratories; Lead; Left; Left Ventricular Dysfunction; Length; Measures; Mediating; Mesenchymal Stem Cells; Methods; Molecular; Muscle Cells; Myocardial; Myocardial Infarction; Myocardial Ischemia; Myocardial perfusion; Myocardium; Natural regeneration; Nuclear; Operative Surgical Procedures; Patients; Perfusion; Phenotype; Population; Pre-Clinical Model; Property; Proto-Oncogene Protein c-kit; Research Personnel; Safety; Source; Staging; Stem cells; Target Populations; Telomerase; Testing; Therapeutic; Tissue Donors; Tissues; Ventricular Dysfunction; Ventricular Function; Work; adult stem cell; aged; base; cardiac repair; cell age; combat; congenital heart disorder; density; improved; induced pluripotent stem cell; innovation; interest; novel; novel strategies; postnatal; prevent; programs; public health relevance; regenerative; repaired; stem; stem cell population; telomere; Address; Adult; Age; Allogenic; Animal Model; Anterior Descending Coronary Artery; Attention; Autologous; Biopsy; Blood Vessels; Cardiac; Cardiac Myocytes; Cell Aging; Cell Cycle; Cell Therapy; Cell Transplantation; Cells; Chronic; Clinical; Complex; Coronary Arteriosclerosis; Coronary Stenosis; Derivation procedure; Development; Elderly; Engraftment; Exhibits; Family suidae; Functional disorder; Future; Heart; Heart Diseases; Heart failure; Injection of therapeutic agent; Investigation; Laboratories; Lead; Left; Left Ventricular Dysfunction; Length; Measures; Mediating; Mesenchymal Stem Cells; Methods; Molecular; Muscle Cells; Myocardial; Myocardial Infarction; Myocardial Ischemia; Myocardial perfusion; Myocardium; Natural regeneration; Nuclear; Operative Surgical Procedures; Patients; Perfusion; Phenotype; Population; Pre-Clinical Model; Property; Proto-Oncogene Protein c-kit; Research Personnel; Safety; Source; Staging; Stem cells; Target Populations; Telomerase; Testing; Therapeutic; Tissue Donors; Tissues; Ventricular Dysfunction; Ventricular Function; Work; adult stem cell; aged; base; cardiac repair; cell age; combat; congenital heart disorder; density; improved; induced pluripotent stem cell; innovation; interest; novel; novel strategies; postnatal; prevent; programs; public health relevance; regenerative; repaired; stem; stem cell population; telomere

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.

描述（由申请人提供）：居民成年心脏干细胞的发现引起了利用心脏内源性再生潜力，以开发基于细胞的疗法以逆转肌细胞损失并改善缺血性心脏病患者的心室功能。从心肌活检中分离出的心圈衍生细胞（CDC）是最近确定的成年干细胞来源，可通过直接分化为心肌细胞和刺激内源性心肌增殖来促进心脏再生并增强收缩功能。为了建立这些初始结果，注意力集中在确定放大CDC介导的心脏修复的策略。一种新颖的方法是在产后早期发育期间利用心脏中心脏细胞的高度增殖表型，这可能为具有优质再生潜力的CDC提供了源头。因此，该提案的目的是检验中心假设，即产后早期心脏发育中源自年轻心脏的CDC优于促进心脏修复的老年成人心脏的CDC。为了检验这一假设，在肾上部给药后，将比较年轻心脏来源的CDC（Y-CDC）和老年心脏衍生的CDC（A-CDC）的疗效。具体而言，AIM 1将检查每个细胞群体在猪内的心肌收缩功能和灌注中的能力，并通过慢性冠状动脉狭窄引起的冬眠心肌。在AIM 2中，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，动员内源性祖细胞并分化为心肌细胞和血管的能力。 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对于患有心脏病的老年人。此外，细胞重新编程方法的进步（例如，诱导的多能干细胞）最终可能使研究人员可以概括老年人的细胞中年轻的CDC表型，最终导致新的策略开发出优化心脏修复并预防左心室功能障碍到临床性心脏失效到临床上的患者患者的临床性心脏失效。