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(由申请人提供)：心力衰竭(HF)是多种心血管疾病的终末期形式，在美国和世界范围内仍然是发病率和死亡率的主要来源。进展为心衰通常是由于心肌梗死(MI)后心脏结构和功能的不良重构所致。其特征是，由于缺血损伤，存活的心肌细胞逐渐丧失，取而代之的是无法支持心脏收缩需求的纤维化瘢痕，导致功能失代偿、病理性肥大和衰竭。在历史上，成年哺乳动物的心脏被认为缺乏在出生后生长或损伤后产生新的心肌细胞的能力，完全依赖于组织纤维化和疤痕作为唯一的愈合手段。然而，在过去的二十年里，越来越多的证据表明，包括人类在内的成年哺乳动物具有适度的心脏再生潜力，这表明丢失的心肌组织的再生是限制心力衰竭进展的潜在治疗途径。然而，心脏的内源性再生能力似乎不足以解决心肌梗死后发生的巨大损伤。更重要的是，内源性心脏再生的潜在分子机制仍未解决。利用抗原标记物(c-Kit、SCA-1和侧群细胞标记物ABCG2)在成人心脏中分离和鉴定多种类型的心脏常驻祖细胞(CPC)引起了人们的极大关注(和几项临床试验)，常驻心肌干细胞是成人心脏心肌细胞更新和替换的潜在重要贡献者。然而，到目前为止，对于在生理或病理条件下，CPC向成人心脏贡献新的心肌细胞的程度还没有达成共识。这在一定程度上是因为该领域在很大程度上采用了体外分离、扩增和移植CPC，但还没有进行明确的遗传学研究来确定这些细胞在体内的生物学作用，在它们的内源生态位内。这项建议旨在解决这一问题，并确定两类细胞-SCA-1+细胞和ABCG2+SP细胞-在正常生理生长期间或心肌梗死后为成人心脏贡献新的心肌细胞的程度。以往的研究表明，Sca1+和ABCG2+细胞在体外具有一定的心肌细胞生成潜能。我们将利用赞助商实验室的转基因小鼠模型，采用遗传谱系追踪的方法，定量评估这些CPC在1)正常生理生长和衰老期间或2)心肌梗死损伤后对体内新心肌细胞形成的贡献和功能意义。赞助商的实验室最近采用了这种遗传学方法来定义c-Kit+CPC(van Berlo et.艾尔大自然。2014年)，并发现c-Kit+细胞主要对血管系统有贡献，但随着年龄的增长和损伤，心肌细胞对心脏的贡献很小。结合这些数据，我们建议的研究将解决心脏再生中一个长期存在的核心问题：常驻心脏祖细胞(CPC)在多大程度上有助于成人心脏在老化期间或损伤后再生的内源性能力？这些研究将有助于阐明成人心脏内在再生能力的分子机制，并为CPC在修复心肌梗死后受损心肌、缓解心力衰竭进展方面的潜在治疗应用提供洞察力。