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

基本信息

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
项目类别：
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

项目摘要

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：心力衰竭（HF），这是美国和世界各地的多个心血管扫描和死亡率的终端形式。 C损伤和用纤维性疤痕替换，以支持心脏的收缩需求，病史和失败。然而，在过去的二十年中，越来越多的证据表明，包括乳腺组织的成年哺乳动物对心脏的再生潜力是一种潜在的限制治疗方法内源性心脏再生的氨基分子分子机制仍未分解。引起了对居民心脏茎/祖细胞的大量关注（和几项临床试验）在成人心脏中，有可能导致心肌细胞转换和替代由于该领域在很大程度上采用了体内分离，因此CPC的扩展，但没有确定的遗传研究一直进行研究，以确定这些细胞在体内的生物学作用，因此该建议旨在解决两类的问题。 CPC -SCA -1+细胞和ABCG2+ SP细胞在正常的生理生长或MI后对成人心脏造成了新的肌细胞。在MI损伤后，这些CPC在体内形成了新的心肌细胞。数据，我们的支撑性研究将解决心脏再生中的一个长期中心问题：居民心脏祖细胞（CPC）在衰老或损伤后造成了成人心脏的贡献？成人心脏，并提供有关CPC潜在治疗应用在MI后受损受损的心肌受损的洞察力，从而减轻了HF的进展。