The Role of Sca-1+ and ABCG2+ Cardiac Progenitor Cells in Endogenous Heart Regeneration

Sca-1 和 ABCG2 心脏祖细胞在内源性心脏再生中的作用

• 批准号: 9249097
• 负责人: Ronald Joseph Vagnozzi
• 金额: $ 5.92万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9249097
• 关键词: 1 year old; ABCG2 gene; Address; Adult; Aging; Alpha Cell; Animals; Attention; Biological; Birth; Cardiac; Cardiac Myocytes; Cardiovascular Diseases; Cause of Death; Cell Lineage; Cells; Cellular Structures; Cicatrix; Clinical; Clinical Trials; Consensus; Data; Elderly; Enterobacteria phage P1 Cre recombinase; Failure; Fibrosis; Flow Cytometry; Future; Genetic; Genetic study; Genomics; Goals; Growth; Growth and Development function; Heart; Heart Transplantation; Heart failure; Histology; Homeostasis; Human; Hypertrophy; In Vitro; Injury; Knock-in; Knock-in Mouse; Label; Mammals; Mediating; Molecular; Morbidity - disease rate; Mus; Muscle Cells; Myocardial Infarction; Myocardial tissue; Myocardium; Natural regeneration; Nature; Pathologic; Patients; Physiological; Population; Proto-Oncogene Protein c-kit; Reporter; Role; Side; Source; Stem cells; Techniques; Testing; Therapeutic; Time; Tissues; Transgenic Mice; United States; cardiac regeneration; clinical application; defined contribution; genetic approach; healing; in vivo; insight; mortality; mouse model; novel; postnatal; public health relevance; regenerative; repaired; response to injury; stem; stem cell therapy; theories; tool

 DESCRIPTION (provided by applicant): Heart failure (HF), which is the end-stage form of multiple cardiovascular diseases, remains a leading source of morbidity and mortality in the United States and worldwide. Progression to HF often results from adverse structural and functional remodeling of the heart following myocardial infarction (MI). This is characterized by the progressive loss of viable cardiomyocytes due to ischemic injury and replacement with a fibrotic scar that is unable to support the contractile needs of the heart, leading to functional decompensation, pathological hypertrophy, and failure. Historically, the adult mammalian heart was thought to lack the capacity to generate new cardiomyocytes following postnatal growth or after injury, relying exclusively on tissue fibrosis and scarring as the only means of healing. However, growing evidence over the past two decades has now demonstrated a modest degree of cardiac regenerative potential in adult mammals including humans, suggesting that regeneration of lost myocardial tissue is a potential therapeutic avenue for limiting HF progression. However, the endogenous regenerative capacity of the heart appears insufficient to resolve the massive injury that occurs post-MI. More importantly, the underlying molecular mechanisms of endogenous cardiac regeneration remain unresolved. The isolation and characterization of several types of cardiac-resident progenitor cells (CPCs) in the adult heart using antigenic markers (c-Kit, Sca-1 and the side population [SP] cell marker ABCG2) has led to considerable attention (and several clinical trials) on resident cardiac stem/progenitor cells a potential significant contributors to cardiomyocyte turnover and replacement in the adult heart. However, as-yet there is no consensus as to the extent that CPCs contribute new cardiomyocytes to the adult heart under physiological or pathological conditions. This is in part because the field has largely employed ex vivo isolation, expansion, and transplantation of CPCs, but no definitive genetic studies have been performed to determine the biological role of these cells in vivo, within their endogenous niches. This proposal seeks to address this issue and define the extent that two classes of CPCs - Sca-1+ cells and ABCG2+ SP cells - contribute new myocytes to the adult heart during normal physiological growth or post-MI. Previous studies have demonstrated that Sca1+ and ABCG2+ CPCs possess some degree of cardiomyogenic potential in vitro. Using transgenic mouse models generated in the Sponsor's lab, we will employ a genetic lineage tracing approach to quantitatively assess the contribution and functional significance of these CPCs to new cardiomyocyte formation in vivo, during 1) normal physiological growth and aging or 2) after MI injury. The Sponsor's lab has recently employed this genetic approach to define the contribution of c-Kit+ CPCs (van Berlo et. al. Nature. 2014), and found that c-Kit+ cells contribute primarily vasculature but a minimal degree of cardiomyocytes to the heart with aging and injury. Taken together with these data, our proposed studies will address a long-standing central question in cardiac regeneration: to what extent do resident cardiac progenitor cells (CPCs) contribute to the endogenous capacity of the adult heart to regenerate during aging or after injury? These studies will serve to both elucidate the molecular mechanisms underlying the intrinsic regenerative capacity of the adult heart, and provide insight as to potential therapeutic application of CPCs in restoring damaged myocardium post-MI, mitigating the progression to HF.

 描述（由适用提供）：心力衰竭（HF）是多种心血管疾病的终阶段形式，仍然是美国和全球发病率和死亡率的主要来源。在心肌梗塞（MI）之后，心脏的不良结构和功能重塑通常导致HF的进展。这的特征是由于缺血性损伤和用无法支持心脏收缩需求的纤维化疤痕替换而逐渐丧失了可行的心肌细胞，从而导致功能不全，病理肥大和失败。从历史上看，成年哺乳动物心脏被认为缺乏产生新心肌细胞或受伤后产生新的心肌细胞的能力，仅依靠组织纤维化和疤痕是唯一的康复手段。然而，在过去的二十年中，越来越多的证据表明，包括人类在内的患者（包括人类）有适度的心脏再生潜在哺乳动物，这表明丧失的心肌组织的再生是限制HF进展的潜在治疗途径。但是，心脏的内源性再生能力似乎不足以解决MI后发生的巨大损伤。更重要的是，内源性心脏再生的潜在分子机制仍未解决。使用抗原标记（C-KIT，SCA-1和侧种群[SP]细胞标记ABCG2）在成人心脏中几种类型的心脏遗留祖细胞（CPC）的隔离和表征，导致对居民心脏干细胞/祖细胞的临床试验引起了相当大的关注（和几个临床试验），这可能是对心脏切割者的重要造成者的造成者，并替换了成年人的心脏切开术和替补。但是，尚未达成共识，即CPC在身体或病理条件下为成年心脏贡献新的心肌细胞。这部分是因为该领域在很大程度上采用了CPC的离体隔离，扩张和移植，但是在其内源性壁ches中没有进行确定这些细胞在体内的生物学作用的确定生物学作用。该建议旨在解决此问题，并确定两类CPCS -SCA -1+细胞和ABCG2+ SP细胞 - 在正常生理生长或MI后为成人心脏贡献新的肌细胞。先前的研究表明，SCA1+和ABCG2+ CPC在体外具有一定程度的心肌生成潜力。使用赞助商实验室中产生的转基因小鼠模型，我们将采用一种遗传谱系追踪方法来定量评估这些CPC对体内新心肌细胞形成的贡献和功能意义，在1）正常的生理生长和年龄在MI损伤后的正常生长和老化。发起人的实验室最近采用了这种遗传方法来定义C-KIT+ CPC的贡献（Van Berlo等人自然，2014年），发现C-KIT+细胞贡献了原发性脉管系统，但对心脏的心肌细胞对心脏的影响很小。综上所述，我们提出的研究将解决心脏再生中一个长期存在的核心问题：居民心脏祖细胞（CPC）在多大程度上有助于成年心脏在衰老期间或受伤后的内源能力？这些研究将既阐明成人心脏内在再生能力的基础的分子机制，又为CPC在恢复MI后恢复受损的心肌的潜在治疗应用提供了洞察力，从而减轻了对HF的进展。