Electrical Stimulation of Human CPCs

人体 CPC 的电刺激

基本信息

批准号：
10592359
负责人：
Joshua Thomas Maxwell
金额：
$ 38.75万
依托单位：
WAKE FOREST UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-02-10 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10592359
关键词：
5 year old Address Adhesions Adhesives Adolescent Adult Aftercare Age Allogenic Autologous Autopsy Binding Biological Assay Biological Response Modifier Therapy Calcium Oscillations Calcium Signaling Cardiac Cardiac Myoblasts Cardiac Myocytes Cardiovascular Diseases Cardiovascular system Cell Adhesion Molecules Cell Extracts Cell Separation Cell Therapy Cells Chemicals Child Childhood Clinical Trials Congenital Heart Defects Data Echocardiography Economic Burden Electric Stimulation Endothelial Cells Engraftment Exposure to Fibroblasts Fibrosis Functional disorder Gene Expression Genes Genetic Engineering Genotype Heart Heart Transplantation Heart failure Histologic Human Hypertrophy In Vitro Injections Integrins Label Measurement Methods Monitor Morbidity - disease rate Muscle Cells Myocardial Infarction Myocardium Natural regeneration Operative Surgical Procedures Paracrine Communication Patients Phenotype Play Population Proliferating Proteins Proto-Oncogene Protein c-kit Publishing Pulmonary artery structure RNA Rattus Regenerative Medicine Regenerative capacity Reverse Transcriptase Polymerase Chain Reaction Role Testing Therapeutic Therapeutic Intervention Treatment Efficacy Up-Regulation Work adult stem cell angiogenesis candidate identification cellular transduction comparison control cytokine effective therapy electrical property exosome genetic manipulation heart function hemodynamics improved in vivo inhibitor insight mortality novel paracrine pediatric heart failure pharmacologic prevent programs public health relevance regeneration potential release factor reparative capacity response small hairpin RNA stem cell therapy stem cells success

项目摘要

PROJECT SUMMARY/ABSTRACT: Nearly 1 in every 120 children born has a congenital heart defect (CHD). While surgical therapy has improved survival, many of these children go on to develop heart failure (HF). The emergence of cardiovascular regenerative medicine as a potential therapeutic strategy for pediatric HF has provided new avenues for treatment. While primarily tried in adults, stem cell therapy is relatively untested in the pediatric population. It is thus critical to develop novel methods of exploring the regenerative potential of these cells to improve therapeutic interventions in the pediatric population. Stem cell based therapies have shown beneficial effects on several cardiovascular diseases in adults, and cardiac-derived c-kit+ progenitor cells (CPCs), a progenitor cell found in the myocardium, have met with early success in a clinical trial in adults. Due to the ability to readily isolate these cells from CHD patients during surgery, their capacity to proliferate in culture, and their ease of manipulation, pediatric CPCs serve as an ideal cell population for regenerative medicine. However, previous studies have shown that unless these cells are extracted at a very young age (<1 month) the therapeutic efficacy of these cells is diminished. With the vast majority of patients undergoing surgery for CHDs >1 month old, finding novel ways to enhance the regenerative potential of these cells would overcome this critical barrier to stem cell therapy and allow for both autologous and allogeneic treatment options in children and adults. It has been shown that the regenerative potential of adult CPCs can be enhanced by ex vivo manipulation. Electrical stimulation (ES) is one treatment known to enhance cardiogenic potential of various adult stem cells; however, the mechanism remains undetermined. Our published data show that pediatric CPCs (isolated from patients between 1-5 years of age) respond to ES by initiating calcium (Ca2+) oscillations making them an ideal population of cells for manipulation by ex vivo ES. Additionally, our data indicate ES enhances both the function and the retention of pediatric CPCs in vivo. The objective of this proposal is to examine the protective/regenerative capacity of pediatric CPCs in response to ES. We aim to characterize the paracrine factors released by ES-treated pediatric CPCs and determine their effect on cardiac cells, characterize the mechanism of enhanced adhesion/retention, and finally determine if ES enhances their function in vivo. Successful completion of this project will provide mechanisms to enhance the therapeutic efficacy of cardiac stem cells, provide autologous and allogeneic treatment options, and advance regenerative medicine. This project also directly addresses a critical barrier in stem cell therapies for pediatric HF by providing autologous and allogeneic treatments using pre-conditioned CPCs. Additionally, our preliminary data suggest our findings may be applicable as a broader therapy for other cardiac indications such as myocardial infarction. Our results will have implications on all cell-based therapies and offer valuable insights into mechanisms to enhance the therapeutic potential of stem/progenitor cells from children to adults.

项目摘要/摘要：每 120 名出生儿童中就有近 1 名患有先天性心脏病 (CHD)。虽然手术治疗提高了生存率，但其中许多儿童继续发展为心力衰竭 (HF)。这心血管再生医学作为儿科心力衰竭潜在治疗策略的出现提供了新的治疗途径。虽然干细胞疗法主要在成人中进行尝试，但在以下领域相对未经测试：儿科人群。因此，开发探索再生潜力的新方法至关重要这些细胞可以改善儿科人群的治疗干预。基于干细胞的疗法有对成人的多种心血管疾病和心脏来源的 c-kit+ 祖细胞显示出有益的作用细胞（CPC）是心肌中发现的一种祖细胞，在成人临床试验中已取得早期成功。由于能够在手术期间轻松地从 CHD 患者中分离出这些细胞，因此它们的增殖能力培养及其易于操作，儿科 CPC 是再生的理想细胞群药品。然而，之前的研究表明，除非这些细胞是在很小的时候提取的（<1 月）这些细胞的治疗功效会减弱。随着绝大多数患者正在接受对 1 个月以上的先天性心脏病进行手术，找到增强这些细胞再生潜力的新方法将克服干细胞治疗的这一关键障碍，并允许自体和同种异体治疗儿童和成人的选择。研究表明，成年 CPC 的再生潜力可以通过离体操作增强。电刺激 (ES) 是一种已知可增强心源性的治疗方法各种成体干细胞的潜力；然而，其机制仍未确定。我们公布的数据显示儿科 CPC（从 1-5 岁患者中分离出来）通过启动钙剂对 ES 做出反应 (Ca2+) 振荡使它们成为离体 ES 操作的理想细胞群。此外，我们的数据表明，ES 增强了儿科 CPC 的功能和体内保留。此举的目的该提案的目的是检查儿科 CPC 对 ES 的保护/再生能力。我们的目标是表征 ES 处理的儿科 CPC 释放的旁分泌因子，并确定它们对心脏的影响细胞，表征增强粘附/保留的机制，并最终确定 ES 是否增强其在体内发挥作用。该项目的成功完成将为加强治疗提供机制心脏干细胞的功效，提供自体和异体治疗选择，并促进再生药品。该项目还直接解决了儿科心力衰竭干细胞疗法的一个关键障碍使用预调节的 CPC 提供自体和同种异体治疗。另外，我们的初步数据表明我们的研究结果可能适用于其他心脏适应症（例如心肌病）的更广泛的治疗梗塞。我们的结果将对所有基于细胞的疗法产生影响，并提供有价值的见解增强干细胞/祖细胞从儿童到成人的治疗潜力的机制。