Biomimetic cardiac patch capable of rapid angiogenesis

能够快速血管生成的仿生心脏补片

• 批准号: 10079400
• 负责人: Mahmood Khan
• 金额: $ 56.51万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-12-15 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10079400
• 关键词: 3-Dimensional; Acute myocardial infarction; Affect; Animal Model; Animals; Anisotropy; Autologous; Biocompatible Materials; Biomimetics; Calcium; Cardiac; Cardiac Myocytes; Cell Survival; Cell Therapy; Cell Transplantation; Cells; Cicatrix; Clinical; Coupling; Diffusion; Distant; EFRAC; Endothelial Cells; Engraftment; Epidemic; Etiology; FGF2 gene; Fibrosis; Gene Expression; Heart; Heart Diseases; Heart Transplantation; Heart failure; Human; In Vitro; Individual; Kinetics; Lead; Modeling; Myocardial; Myocardial Infarction; Myocardial Ischemia; Myocardial dysfunction; Myocardial tissue; Myocardium; Natural regeneration; Nutrient; Outcome; Oxygen; Performance; Phenotype; Pluripotent Stem Cells; Property; Rattus; Structure; Testing; Thick; Tissues; Translating; Translations; Transplantation; angiogenesis; base; blood vessel development; cardiac implant; cardiac regeneration; cell motility; functional loss; heart damage; heart dimension/size; heart function; improved; in vivo; induced pluripotent stem cell; innovation; ischemic cardiomyopathy; nanofiber; non-invasive monitor; novel; paracrine; protein expression; release factor; repaired; scaffold; stem cell therapy; tissue oxygenation

ABSTRACT Heart failure is on the rise in epidemic global proportions affecting more than 23 million people worldwide including 5.8 million individuals in the US alone. Acute myocardial infarction (MI) leading to ischemic cardiomyopathy is the most common etiology for decreased ejection fraction heart failure. Cardiomyocytes derived from the human inducible pluripotent stem cells (hiPSC-CMs) are promising as a novel autologous cell- based therapy in heart disease. The current obstacles for cardiac regeneration using stem-cell based therapies include cell survival and maturity, anisotropic structure and alignment of elongated cardiomyocytes, electro-mechanical integration of the cardiac patch with the native myocardium, and rapid angiogenesis to support cardiomyocytes in the regenerating myocardium. The main objective of this proposal is to develop a thick mature and functional cardiac tissue that not only has the anisotropy of the native tissue but also stimulates rapid angiogenesis (1-week). We hypothesize that a combination of a functional multi-layered hiPSC-CMs cardiac patch paired with a bFGF scaffold significantly improves the early and late cardiomyocyte survival and promotes rapid angiogenesis. This hypothesis will be tested in the following three specific aims; Aim 1) This aim will determine the maturity, contractile function, and cell survivability of a hiPSC-CMs multi- layered aligned nanofiber cardiac patch in vitro, Aim 2) This aim will establish the efficacy of bFGF releasing scaffolds to enhance hiPSC-CMs survival and promote rapid angiogenesis in simulated ischemic conditions in vitro, Aim 3) This aim will determine efficacy of the transplanted multi-layered hiPSC-CMs cardiac patch paired with bFGF scaffold following myocardial infarction on cardiac function, cell engraftment, angiogenesis, tissue oxygenation and electro-mechanical integration, in an in vivo rat model of MI. Overall, this proposal will establish an innovative myocardial cell-based therapeutic strategy based on, (i) the combination of human iPSC-derived terminal differentiated cardiomyocytes with a biodegradable aligned nanofiber scaffold, (ii) bFGF- releasing scaffold to enhance early cell survival and rapid angiogenesis, and (iii) the non-invasive monitoring of myocardial tissue oxygenation and cell engraftment in vivo. The outcome of this project will enable us to develop a novel cardiac patch for translation into a large animal clinical model of MI for repairing the damaged heart.

摘要 心力衰竭在全球范围内的流行比例正在上升，影响全球2300多万人 其中仅美国就有580万人。急性心肌梗死（MI）导致缺血性 心肌病是射血分数降低的心力衰竭的最常见病因。心肌细胞 来源于人诱导性多能干细胞（hiPSC-CM）的细胞作为一种新的自体细胞是有前途的， 心脏病的基础治疗目前使用干细胞进行心脏再生的障碍 治疗包括细胞存活和成熟，各向异性结构和伸长心肌细胞的排列， 心脏补片与天然心肌的机电整合，以及快速血管生成， 支持心肌细胞再生。这项建议的主要目的是制定一项 不仅具有天然组织的各向异性， 刺激快速血管生成（1周）。我们假设，一个功能多层次的组合， hiPSC-CMs心脏补片与bFGF支架配对显著改善早期和晚期心肌细胞 存活并促进快速血管生成。这一假设将在以下三个具体目标中得到检验： 目的1）该目的将确定hiPSC-CM的成熟度、收缩功能和细胞存活能力， 目的2）建立体外释放bFGF的方法 在模拟缺血条件下， 3）该目的将确定移植的多层hiPSC-CM心脏补片配对的功效。 bFGF支架对心肌梗死后心功能、细胞植入、血管生成、组织 氧合和机电一体化，在MI的体内大鼠模型。总的来说，这项建议将 建立一种基于心肌细胞的创新治疗策略，其基础是：（i）人 iPSC衍生的终末分化的心肌细胞与可生物降解的对齐的支架，（ii）bFGF- 释放支架以增强早期细胞存活和快速血管生成，和（iii）非侵入性监测 心肌组织氧合和体内细胞植入。该项目的成果将使我们能够 开发一种新的心脏补片，用于转化为MI的大型动物临床模型，用于修复受损的 心

项目成果

Pluripotent stem cell-induced skeletal muscle progenitor cells with givinostat promote myoangiogenesis and restore dystrophin in injured Duchenne dystrophic muscle.

• DOI: 10.1186/s13287-021-02174-3
• 发表时间: 2021-02-12
• 期刊: Stem cell research & therapy
• 影响因子: 7.5
• 作者: Xuan W;Khan M;Ashraf M
• 通讯作者: Ashraf M

Dual-Specificity Phosphatase 4 Overexpression in Cells Prevents Hypoxia/Reoxygenation-Induced Apoptosis via the Upregulation of eNOS.

• DOI: 10.3389/fcvm.2017.00022
• 发表时间: 2017
• 期刊: Frontiers in cardiovascular medicine
• 影响因子: 3.6
• 作者: Dougherty JA;Kilbane Myers J;Khan M;Angelos MG;Chen CA
• 通讯作者: Chen CA

Preclinical Large Animal Porcine Models for Cardiac Regeneration and Its Clinical Translation: Role of hiPSC-Derived Cardiomyocytes.

• DOI: 10.3390/cells12071090
• 发表时间: 2023-04-05
• 期刊: Cells
• 影响因子: 6

Supplemental Oxygen Protects Heart Against Acute Myocardial Infarction.

• DOI: 10.3389/fcvm.2018.00114
• 发表时间: 2018
• 期刊: Frontiers in cardiovascular medicine
• 影响因子: 3.6
• 作者: Prabhat AM;Kuppusamy ML;Naidu SK;Meduru S;Reddy PT;Dominic A;Khan M;Rivera BK;Kuppusamy P
• 通讯作者: Kuppusamy P

Current Status and Potential Therapeutic Strategies for Using Non-coding RNA to Treat Diabetic Cardiomyopathy.

使用非编码RNA治疗糖尿病心肌病的当前状态和潜在的治疗策略。

• DOI: 10.3389/fphys.2020.612722
• 发表时间: 2020
• 期刊: Frontiers in physiology
• 影响因子: 4
• 作者: Rai AK;Lee B;Gomez R;Rajendran D;Khan M;Garikipati VNS
• 通讯作者: Garikipati VNS