Nanowired human isogenic cardiac organoids to treat acute myocardial ischemia/reperfusion injuries

纳米线人类同基因心脏类器官治疗急性心肌缺血/再灌注损伤

• 批准号: 10721208
• 负责人: Ying Mei
• 金额: $ 37.99万
• 依托单位: CLEMSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10721208
• 关键词: Acceleration; Acute; Address; Allogenic; Animal Model; Animals; Attention; Bovine Serum Albumin; Cardiac; Cardiac Myocytes; Cardiovascular Diseases; Cause of Death; Cell Survival; Cells; Chemicals; Clinical; Clinical Trials; Data; Development; Dissociation; Electric Conductivity; Endothelial Cells; Endothelium; Engraftment; Family suidae; Female; Fibroblasts; Goals; Harvest; Heart; Heart Injuries; Human; Immune; Implant; Injections; Ischemia; Major Histocompatibility Complex; Methods; Modeling; Myocardial Infarction; Myocardial Reperfusion Injury; Myocardium; Organoids; Pathologic; Patients; Prognosis; Proteins; Rattus; Recovery of Function; Regenerative capacity; Reperfusion Injury; Reperfusion Therapy; Research; Risk; Silicon; Stromal Cells; Structure; System; Translating; Transplantation; Treatment Efficacy; Variant; Vascularization; cardiac repair; catalyst; clinical development; clinical translation; fabrication; functional improvement; functional restoration; human pluripotent stem cell; implantation; in vivo; innovation; male; nanowire; percutaneous coronary intervention; porcine model; public health relevance

Project Summary: In the U.S., there are more than 735,000 myocardial infarctions (MI) each year. While percutaneous coronary intervention (PCI) has significantly reduced acute adverse repones, the long-term prognosis for post-ischemia/reperfusion (I/R) patients remains poor. Due to the limited regenerative capacity of human hearts, human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) have received significant attention due to their proven capacity to restore contractile function upon transplantation to injured hearts in various mammalian models, leading to multiple ongoing clinical trials. However, the current transplantation approach mainly relies on dissociated hPSC-CMs, leading to low cell survival, moderate functional improvement, arrhythmogenic risk, and poor scalability. To address these challenges, our lab developed nanowired, pre- vascularized human cardiac organoids composed of hPSC-CMs, human primary cardiac fibroblasts, endothelial cells, stromal cells, and electrically conductive silicon nanowires (e-SiNWs). Endothelial cells are used to induce vasculature formation within the organoids, and e-SiNWs are added to create an electrically conductive microenvironment to facilitate hPSC-CM contractile development and their electrical integration with the host myocardium. Our preliminary in vivo data showed that nanowired organoids illustrated robust hPSC- CM engraftment and superior functional recovery. The major barriers in their clinical translation include: 1) the use of animal proteins in the cell and organoid culture and 2) the lack of functional benefit demonstration in a large animal model. Replacing human primary cells with isogenic hPSC-derived cells for organoid fabrication would reduce batch-to-batch variations and enhance immune compatibility through Major Histocompatibility Complex (MHC) matching hPSC donors with human recipients. In addition, while the current hPSC-CM implantation strategy has been focused on intramyocardial injection, developing an effective approach for intracoronary delivery of the organoids will accelerate their clinical translation. The goal of this proposal is to develop clinical-grade hPSC cardiac organoids and demonstrate their functional benefits with a large animal model to generate enabling data for IND submission. The central hypothesis of this proposal is the nanowired isogenic hPSC cardiac organoids provide a scalable system to both efficiently and effectively implant hPSC-CMs for cardiac repair. The proposal is innovative in that we will 1) derive isogenic hPSC-derived cells in xeno-free, chemically defined conditions to develop clinical-grade cardiac organoids for implantation and 2) leverage the size and the endothelial lumen-like structures in the organoids to develop an effective intracoronary delivery strategy. Accordingly, we will pursue the following 2 aims: 1) Fabricate and characterize nanowired human cardiac organoids using isogenic cardiac cells derived from hPSCs in xeno-free, chemically defined conditions, and 2) Determine the therapeutic efficacy of the nanowired isogenic hPSC cardiac organoids with a porcine I/R (ischemia/reperfusion) model.

项目摘要：在美国，每年有超过735,000个心肌梗塞（MI）。尽管 经皮冠状动脉干预（PCI）显着降低了急性不良重复，长期 缺血后/再灌注（I/R）患者的预后仍然很差。由于再生能力有限 人心，人类多能干细胞衍生的心肌细胞（HPSC-CMS）已获得显着 由于其可靠的能力恢复收缩功能后，注意到受伤的心脏的关注能力 各种哺乳动物模型，导致多次正在进行的临床试验。但是，当前的移植 方法主要依赖于解离的HPSC-CM，导致细胞存活低，功能改善， 心律失常风险和较差的可伸缩性。为了应对这些挑战，我们的实验室开发了纳米，预先的 由HPSC-CM，人类原发性心脏成纤维细胞组成的血管化人心脏器官， 内皮细胞，基质细胞和导电硅纳米线（E-SINWS）。内皮细胞是 用于诱导器官内部的脉管形成，并添加电子固定以产生电气 导电微环境，以促进HPSC-CM收缩的发育及其电气整合 主机心肌。我们的初步体内数据表明，纳米器官说明了强大的HPSC- CM植入和卓越的功能恢复。其临床翻译的主要障碍包括：1） 在细胞和器官培养中使用动物蛋白，2）在A中缺乏功能益处的证明 大动物模型。用等生HPSC衍生的细胞代替人类原代细胞进行器官制造 通过主要的组织相容性，将减少批处理变化并增强免疫兼容性 将HPSC供体与人类受体相匹配的复杂（MHC）。另外，当前的HPSC-CM 植入策略一直集中在心脏内注射上，开发了一种有效的方法 类器官的冠状动脉递送将加速其临床翻译。该提议的目的是 开发临床级HPSC心脏器官，并通过大动物证明其功能益处 模型生成启用数据以进行IND提交。该提议的中心假设是纳米 等生HPSC心脏器官为有效植入的HPSC-CMS提供了可扩展的系统 用于心脏修复。该提案具有创新性，因为我们将1）在无Xeno的无异构HPSC衍生细胞中得出无异构的细胞， 化学定义的条件以开发临床级心脏器官进行植入，2）利用 大小和类器官中的内皮管腔样结构，以形成有效的冠状体内递送 战略。因此，我们将追求以下2个目标：1）捏造和描述纳米人的人 心脏类器官使用源自HPSC的同源性心脏细胞，在无XENO，化学定义的条件下， 和2）确定纳米的同源性HPSC心脏器官的治疗功效 （缺血/再灌注）模型。