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.

抽象的 全球流行病的流行比例正在上升，全球影响超过2300万人 仅在美国就包括580万个人。急性心肌梗塞（MI）导致缺血性 心肌病是减少射血分数心力衰竭的最常见病因。心肌细胞 源自人类诱导的多能干细胞（HIPSC-CM）是一种新型自体细胞 - 基于心脏病的疗法。使用基于干细胞的心脏再生的当前障碍 疗法包括细胞存活和成熟度，各向异性结构以及伸长心肌细胞的比对， 心脏斑块与天然心肌的电力整合，以及快速的血管生成 在再生心肌中支持心肌细胞。该提议的主要目的是开发 厚实的成熟和功能性心脏组织，不仅具有天然组织的各向异性，而且还具有 刺激快速血管生成（1周）。我们假设功能多层的组合 HIPSC-CMS心脏贴片与BFGF脚手架配对可显着改善早期和晚期心肌细胞 生存并促进快速血管生成。该假设将在以下三个特定目标中进行检验。 目标1）此目标将确定HIPSC-CMS多的成熟度，收缩功能和细胞的存活率 分层对齐的纳米纤维心脏贴片在体外，目标2）此目标将确定BFGF释放的功效 脚手架以增强HIPSC-CMS存活并促进模拟缺血条件中的快速血管生成 体外，目标3）此目标将确定移植的多层HIPSC-CMS心脏贴片的功效 在心肌梗死后，BFGF支架对心脏功能，细胞植入，血管生成，组织 在Mi的体内大鼠模型中，氧合和电力整合。总体而言，该建议将 建立基于（i）人类组合的创新性心肌细胞的治疗策略 IPSC衍生的末端分化心肌细胞具有可生物降解的对齐纳米纤维支架，（ii）BFGF- 释放支架以增强早期细胞存活和快速的血管生成，以及（iii）非侵入性监测 体内心肌组织氧合和细胞植入。该项目的结果将使我们能够 开发新的心脏斑块，以转化为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

CLIC4 localizes to mitochondrial-associated membranes and mediates cardioprotection.

• DOI: 10.1126/sciadv.abo1244
• 发表时间: 2022-10-21
• 期刊: Science advances
• 影响因子: 13.6