Integrated Cellular and Tissue Engineering for Ischemic Heart Disease

缺血性心脏病的综合细胞和组织工程

• 批准号: 10425390
• 负责人: Nenad Bursac
• 金额: $ 116.45万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-15 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10425390
• 关键词: Action Potentials; Address; Adult; Animal Model; Animals; Arrhythmia; Bioenergetics; Biomedical Engineering; Blood Vessels; CRISPR/Cas technology; Cardiac; Cardiac Myocytes; Cardiovascular system; Cause of Death; Cell Line; Cell Therapy; Cell Transplantation; Cells; Cicatrix; Clinic; Clinical; Clinical Trials; Clustered Regularly Interspaced Short Palindromic Repeats; Communities; Electrophysiology (science); Endothelial Cells; Engineering; Engraftment; Family suidae; Fibroblasts; Functional disorder; Generations; Genetic Engineering; Genomics; Goals; HLA Antigens; Heart; Heart failure; Histocompatibility Antigens Class I; Human; Immune Tolerance; Immune system; Immunosuppression; Impairment; Implant; In Vitro; Infarction; Knock-out; Knowledge; Left Ventricular Remodeling; Libraries; Longevity; Magnetic Resonance Imaging; Mechanics; Mediating; Metabolism; Modality; Modeling; Mus; Myocardial; Myocardial Infarction; Myocardial Ischemia; Myocardial perfusion; Myocardial tissue; Myocardium; NMR Spectroscopy; Natural regeneration; Optics; Pathologic; Patients; Pluripotent Stem Cells; Population; Public Health; Quality of life; Research; Site; Sodium Channel; Source; Standardization; Stress; Technology; Testing; Therapeutic; Therapeutic Effect; Tissue Engineering; Tissues; Translating; Translations; Transplantation; Tumorigenicity; United States; Vascularization; base; capillary bed; cardiac repair; cardiac tissue engineering; cell type; cellular engineering; clinically translatable; engineered stem cells; exosome; genetically modified cells; human pluripotent stem cell; humanized mouse; immunogenicity; immunosuppressed; improved; in vivo; induced pluripotent stem cell; mouse model; novel; novel strategies; novel therapeutic intervention; paracrine; personalized medicine; pluripotency; porcine model; pre-clinical; pre-clinical research; repaired; response; scale up; stem cells

ABSTRACT Ischemic heart disease continues to have a tremendous impact on public health, shortening lifespan and impairing the quality of life. The inability of the adult human myocardium to undergo regeneration after a myocardial infarction has inspired research using cell therapy for myocardial repair. However, clinical trials to date have shown modest or no benefit, suggesting the need to consider other cell sources and approaches. In large animal models, derivatives of human pluripotent stem cells have provided promising results, but the grafts have generally been small, transient, and of limited functional benefit. In addition, there remain important questions regarding cardiac cells derived from iPSCs, including the optimal delivery strategy, immunogenicity, maturity, and the ability to couple effectively to the native myocardium without causing arrhythmias. In this proposal, three integrated projects will address these challenges and advance toward the long-term goal of utilizing a functional human cardiac tissue patch (hCTP) for repair of ischemic myocardium. The first project aims to generate novel cell populations, including induced cardiac progenitor cells and genetically engineered cell lines that will be evaluated for their immunogenicity in a novel humanized mouse model. These and other cell products, including commercially available sources, will be utilized to generate large vascularized hCTPs in the second project. The third project will utilize a porcine post-infarction model to test hCTPs and optimize electrical and vascular integration as assessed by optical mapping technology and MRI/NMR spectroscopy, respectively. These studies will overcome critical barriers to generating large, fully functional human cardiac tissues that can be integrated safely into the native myocardium to provide a powerful new approach for treatment of advanced ischemic heart disease.

抽象的 缺血性心脏病继续对公共卫生，寿命缩短和 损害生活质量。成年人类心肌无法在 心肌梗死激发了使用细胞疗法进行心肌修复的研究。但是，临床试验 日期显示出适度或没有好处，表明需要考虑其他细胞来源和方法。 在大型动物模型中，人多能干细胞的衍生物提供了令人鼓舞的结果，但是 移植物通常很小，瞬态，功能益处有限。此外，还有 有关源自IPSC的心脏细胞的重要问题，包括最佳输送策略， 免疫原性，成熟度以及有效夫妇在不引起的本地心肌的能力 心律不齐。在此提案中，三个集成项目将解决这些挑战，并朝着 利用功能性人类心脏组织（HCTP）修复缺血性心肌的长期目标。 第一个项目旨在产生新的细胞群体，包括诱发心脏祖细胞和 基因工程细胞系将在新型人源性小鼠中评估其免疫原性 模型。这些和其他细胞产品（包括市售的来源）将用于生成 第二个项目中的大型血管化HCTP。第三个项目将利用猪后界限模型 测试HCTP并优化通过光学映射技术评估的电气和血管整合 和MRI/NMR光谱。这些研究将克服产生大型的关键障碍 功能齐全的人类心脏组织，可以安全地整合到天然心肌中以提供 强大的新方法治疗晚期缺血性心脏病。

项目成果

Differential Response of Engineered Human Cardiac Tissues to Delta and Omicron COVID-19 Virus.

• DOI: 10.1161/jaha.123.029390
• 发表时间: 2023-06-20
• 期刊: JOURNAL OF THE AMERICAN HEART ASSOCIATION
• 影响因子: 5.4
• 作者: Zhang, Qiao;Zhan, Ren-Zhi;Patsy, Marisa;Li, Binjie;Chen, Yifan;Lipes, Barbara D.;Bursac, Nenad;Truskey, George A.
• 通讯作者: Truskey, George A.

Fibroblast Growth Factor (FGF) 23 and FGF Receptor 4 promote cardiac metabolic remodeling in chronic kidney disease.

成纤维细胞生长因子 (FGF) 23 和 FGF 受体 4 促进慢性肾病患者的心脏代谢重塑。

• DOI: 10.21203/rs.3.rs-3705543/v1
• 发表时间: 2023
• 期刊: Research square
• 作者: Fuchs,MichaelaA;Burke,EmilyJ;Latic,Nejla;Murray,Susan;Li,Hanjun;Sparks,Matthew;Abraham,Dennis;Zhang,Hengtao;Rosenberg,Paul;Hänzelmann,Sonja;Hausmann,Fabian;Huber,Tobias;Erben,Reinhold;Fisher-Wellman,Kelsey;Bursac,Nenad;Wolf
• 通讯作者: Wolf

Nox2 contributes to the arterial endothelial specification of mouse induced pluripotent stem cells by upregulating Notch signaling.

Nox2 通过上调 Notch 信号传导促进小鼠诱导多能干细胞的动脉内皮规范

• DOI: 10.1038/srep33737
• 发表时间: 2016-09-19
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Kang X;Wei X;Wang X;Jiang L;Niu C;Zhang J;Chen S;Meng D
• 通讯作者: Meng D

BRG1 is a biomarker of hypertrophic cardiomyopathy in human heart specimens.

• DOI: 10.1038/s41598-022-11829-x
• 发表时间: 2022-05-17
• 期刊: Scientific reports
• 影响因子: 4.6

Toward improved understanding of cardiac development and congenital heart disease: The advent of cardiac organoids.

• DOI: 10.1016/j.jtcvs.2022.02.028
• 发表时间: 2022-12
• 期刊: JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY
• 影响因子: 6
• 作者: Scherba, Jacob C.;Karra, Ravi;Turek, Joseph W.;Bursac, Nenad
• 通讯作者: Bursac, Nenad