Nanowired human cardiac spheroids for heart repair

用于心脏修复的纳米线人类心脏球体

• 批准号: 9384348
• 负责人: Ying Mei
• 金额: $ 39.21万
• 依托单位: CLEMSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9384348
• 关键词: Address; Adult; Affect; Amination; Amines; Anoikis; Arrhythmia; Attention; Calcium; Cardiac; Cardiac Myocytes; Cardiovascular Diseases; Cause of Death; Cell Death; Cell Transplantation; Cell-Cell Adhesion; Cells; Cellular Morphology; Charge; Chemistry; Clinical; Data; Dimensions; Electric Conductivity; Electric Stimulation; Electrophysiology (science); Engraftment; Foundations; Gene Proteins; Goals; Harvest; Heart; Heart failure; Human; In Vitro; Injectable; Integrin Binding; Ischemia; Literature; Lung; Mechanics; Modification; Myocardium; Nude Rats; Organ; Paper; Pharmaceutical Preparations; Phenotype; Play; Publications; Rattus; Reperfusion Therapy; Research; Role; Series; Silicon; Solid; Surface; Surface Properties; Techniques; Technology; Time; Tissues; Translating; Transplantation; Ventricular; cardiac repair; disability; functional improvement; improved; in vivo; induced pluripotent stem cell; injured; innovation; nanowire; protein expression; public health relevance; regenerative; repaired; self assembly; synergism; Address; Adult; Affect; Amination; Amines; Anoikis; Arrhythmia; Attention; Calcium; Cardiac; Cardiac Myocytes; Cardiovascular Diseases; Cause of Death; Cell Death; Cell Transplantation; Cell-Cell Adhesion; Cells; Cellular Morphology; Charge; Chemistry; Clinical; Data; Dimensions; Electric Conductivity; Electric Stimulation; Electrophysiology (science); Engraftment; Foundations; Gene Proteins; Goals; Harvest; Heart; Heart failure; Human; In Vitro; Injectable; Integrin Binding; Ischemia; Literature; Lung; Mechanics; Modification; Myocardium; Nude Rats; Organ; Paper; Pharmaceutical Preparations; Phenotype; Play; Publications; Rattus; Reperfusion Therapy; Research; Role; Series; Silicon; Solid; Surface; Surface Properties; Techniques; Technology; Time; Tissues; Translating; Transplantation; Ventricular; cardiac repair; disability; functional improvement; improved; in vivo; induced pluripotent stem cell; injured; innovation; nanowire; protein expression; public health relevance; regenerative; repaired; self assembly; synergism

Project Summary: Cardiovascular disease is the leading cause of death and disability worldwide. Due to the limited regenerative capacity of adult hearts, human induced pluripotent stem cells (hiPSCs) have received significant attention due to their proven ability to derive functional cardiomyocytes (hiPSC-CMs). Despite the progress, the current inability to effectively deliver and integrate hiPSC-CMs into damaged myocardium has limited the applications of hiPSC technology in cardiac repair. The current strategies are limited by 1) low cell retention and survival after cell transplantation, and 2) unspecific and immature phenotype of the current hiPSC-CMs. To address these challenges, we pioneered the use of electrically conductive silicon nanowires (e-SiNWs) to facilitate self-assembly of hiPSC-CMs to form nanowired hiPSC cardiac spheroids. The addition of e-SiNWs was found to enhance electrical conduction in the spheroids and improve their function. In addition, our recent publication showed electrical stimulation synergizes with e-SiNWs to promote ventricular lineage specification and cellular maturation (i.e., ventricular maturation) and reduce the spontaneous beating of the hiPSC cardiac spheroids in in vitro culture. Further, our in vivo studies showed the nanowired spheroids improve cell retention and engraftment with host myocardium after transplantation, presumably due to their 3D microtissue configuration and the e-SiNW enhanced electrical integration. Our long-term goal is to translate nanowired hiPSC cardiac spheroid technology into a clinical therapy for heart repair. The goal of this proposal is to 1) study the effects of the intrinsic (electrical and surface) properties of e-SiNWs and extrinsic factor (electrical stimulation) on ventricular maturation of the nanowired spheroids, and 2) examine the effects of ventricular maturity of the nanowired spheroids on their engraftment. The central hypothesis of this proposal is the nanowired hiPSC cardiac spheroids provide a powerful platform to 1) accelerate ventricular maturation of hiPSC-CMs in vitro and 2) improve the retention, engraftment and integration of hiPSC-CMs with host myocardium in vivo. The proposal is innovative in that, for the first time, we prepare hiPSC cardiac microtissues with defined ventricular maturity for transplantation. Accordingly, we will pursue three specific aims: 1) Elucidate the mechanisms of the interactions between e-SiNWs and hiPSC-CMs, 2) Further advance ventricular maturation of nanowired hiPSC cardiac spheroids through long-term electrical stimulations, and 3) Examine in vivo efficacy of the nanowired hiPSC cardiac spheroids in both healthy (Aim 3a) and injured (Aim 3b) rat hearts. The completion of the proposed research would, for the first time, allow us to 1) produce hiPSC-CMs with controlled ventricular maturity, 2) develop a set of quantitative criteria to assess ventricular maturity of hiPSC-CMs for transplantation, and 3) identify a suitable range of ventricular maturity of hiPSC- CMs for transplantation. Also, it will lay down a solid foundation to establish the use of electrically stimulated, nanowired hiPSC cardiac spheroids as an innovative platform to deliver hiPSC-CMs to treat heart failure.

项目摘要：心血管疾病是全球死亡和残疾的主要原因。由于 成人心脏的再生能力有限，人类诱导的多能干细胞（HIPSC）已收到 由于其可靠的能力得出功能性心肌细胞（HIPSC-CMS），因此非常关注。尽管有 进展，目前无法有效传递和整合HIPSC-CMS 限制HIPSC技术在心脏修复中的应用。当前的策略受到1）低细胞的限制 细胞移植后的保留和存活，2）电流的未特异性和未成熟表型 HIPSC-CMS。为了应对这些挑战，我们开创了使用导电硅纳米线的使用 （e-sinws）促进hipsc-CM的自组装形成纳米hipsc心脏球体。加法 发现E-sinws可增强球体中的电传导并提高其功能。此外， 我们最近的出版物显示电刺激与E-SINW协同促进心室谱系 规格和细胞成熟（即心室成熟），并减少自发跳动 HIPSC心脏球体在体外培养中。此外，我们的体内研究表明纳米球体 移植后改善细胞保留和植入宿主心肌，大概是由于其3D 微动物配置和E-SINW增强的电气整合。我们的长期目标是翻译 纳米的HIPSC心脏球体技术进入临床治疗以进行心脏修复。目标的目标 提案是1）研究E-sinws和外部的固有（电和表面）特性的影响 因子（电刺激）对纳米球体的心室成熟的因素，2）检查效果 纳米球体植入的纳米球体的心室成熟度。中心假设 提案是纳米hipsc心脏球体提供的强大平台1） HIPSC-CM在体外成熟和2）改善HIPSC-CMS的保留，植入和整合 体内托管心肌。该提案是创新的，因为我们首次准备HIPSC心脏 微动物具有定义的心室成熟度以进行移植。因此，我们将追求三个特定的 目的：1）阐明E-SINWS和HIPSC-CMS之间相互作用的机制，2）进一步推进 通过长期电刺激，纳米hipsc心脏球体的心室成熟，3） 检查健康（AIM 3A）和受伤的纳米hipsc心脏球体的体内功效（AIM 3b）大鼠心。拟议研究的完成将首次允许我们进行1）生产 HIPSC-CM具有受控心室成熟度的HIPSC-CM，2）制定一组定量标准来评估心室 HIPSC-CM的成熟度进行移植，3）确定适当的hipsc-室成熟度范围 CMS进行移植。此外，它将奠定坚实的基础，以建立电刺激的使用， 纳米hipsc心脏球体是一种创新平台，可提供HIPSC-CMS治疗心力衰竭。