Endogenous and exogenous mechanisms that promote myocardial remuscularization in post infarction LV remodeling

梗死后左室重构中促进心肌再肌化的内源性和外源性机制

• 批准号: 10302748
• 负责人: Jianyi Zhang
• 金额: $ 51.98万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-10 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10302748
• 关键词: 3-Dimensional; Acute myocardial infarction; Adult; Animals; Apoptotic; Arrhythmia; Back; Biomedical Engineering; Birth; Blood Vessels; CCND2 gene; Cardiac; Cardiac Myocytes; Cell Cycle; Cell Line; Cell Nucleus; Cell Transplantation; Cells; Cicatrix; Congestive Heart Failure; Cues; Dilatation - action; Dimensions; Electric Stimulation; Endothelium; Engineering; Engraftment; Family suidae; Fibroblasts; Functional disorder; Generations; Heart; Heart failure; Human; Human Engineering; Imaging technology; Infarction; Injury; Left; Left Ventricular Remodeling; Left ventricular structure; Mammals; Measurement; Molecular; Molecular Biology; Mus; Muscle Cells; Myocardial; Myocardial tissue; Myocardium; Natural regeneration; Neonatal; Optics; Patients; Periodicity; Pilot Projects; Proliferating; Protocols documentation; Public Health; RNA; Recovery; Regimen; Regulatory Pathway; Reporting; Rodent Model; Signal Pathway; Site; Smooth Muscle; Stretching; Surface; Techniques; Technology; Testing; Thick; Tissue Engineering; Tissues; Transplantation; Vascularization; Ventricular; Ventricular Arrhythmia; base; cardiac tissue engineering; cell type; clinically relevant; effectiveness evaluation; endothelial stem cell; functional improvement; heart function; improved; in vivo; induced pluripotent stem cell; injured; mature animal; molecular imaging; myocardial injury; novel; overexpression; porcine model; postnatal; prevent; promoter; regeneration potential; repaired; restoration; success; transcriptome sequencing

Endogenous and exogenous mechanisms that promote myocardial remuscularization in post infarction LV remodeling Summary / Abstract The molecular and cellular basis for the progressive heart failure is the result of the inability of damaged and apoptotic myocytes to be replaced. While a number of cell- and tissue-based therapies can limit this dysfunction, the proportion of cells that survive at the site of administration for more than a few weeks after transplantation is extremely low. As such, substantial remuscularization of the infarcted region has rarely been reported; and when limited remuscularization has been reported, it is frequently accompanied by potentially lethal ventricular arrhythmias of unknown mechanism. This proposal aims at remuscularization of the injured ventricle from “within” by identifying key regulators of the cell cycle and by promoting the native cardiomyocyte (CM) reenter the cell cycle, and from “outside” by transplanting bioengineered cardiac muscle patch (hCMP) with the key regulators of CM cell cycle upregulated, and with that incorporate a functional vascular network and recapitulate some of the key micro environmental cues of native heart tissue. We recently established a novel hiPSC cell line with MHC-driven overexpression of a key regulator of CM: CCND2 (hiPSC-MHC-CCND2OE), which can remuscularize injured ventricle in rodent model. The central objective of this proposal is to “turn back the clock” of myocyte cell cycle for myocardial repair. The specific Aims ( SA) are: SA1: Identifying the key regulators that promote cell-cycle activity in the hearts of early neonatal pigs after myocardial injury. We will: 1) using state-of-the-art molecular biology and imaging technologies, and the single cell/nucleus RNA sequencing (scRNAseq or snRNAseq) technology to demonstrate these key regulators/signaling pathways that control the myocyte cell cycle; and2) test remuscularization of injured ventricle by manipulating the key regulators using either targeted modRNA or AAV9 to selectively modify these regulators in adult pigs with AMI. SA2a. Engineering hCMPs of previously unattainable size and thickness that are functionally mature and primed for in-vivo vascularization. SA2b. Evaluating the effectiveness of our hCMP constructs for myocardial recovery and remuscularization in a large-animal (swine) model of myocardial injury. We will use state-of-the-art techniques of optical mapping in combination with the 3-dimensional intramural cardiac mapping to delineate potential arrhythmia mechanisms over the entire left-ventricular surface and transmurally.

促进术后心肌再肌化的内源性和外源性机制 梗死左心室重构 摘要/摘要 进行性心力衰竭的分子和细胞基础是受损的功能丧失的结果。 和凋亡的肌细胞被替换。虽然许多基于细胞和组织的疗法可以限制这种情况 功能障碍，即给药后在给药部位存活数周以上的细胞比例 移植率极低。因此，梗塞区域的大量肌肉重建很少见 被举报；当报道了有限的再肌化时，它经常伴随着 机制未知的潜在致命性室性心律失常。该提案旨在重新肌肉化 通过识别细胞周期的关键调节因子并促进天然的心室从“内部”修复受损的心室 心肌细胞（CM）通过移植生物工程心肌从“外部”重新进入细胞周期 补丁（hCMP）与CM细胞周期的关键调节剂上调，并与其中包含功能 血管网络并概括了天然心脏组织的一些关键微环境线索。我们 最近建立了一种新型 hiPSC 细胞系，其 MHC 驱动的 CM 关键调节因子 CCND2 过表达 （hiPSC-MHC-CCND2OE），可以使啮齿动物模型中受伤的心室重新肌肉化。的中心目标 这个建议是让肌细胞的细胞周期“倒转”以进行心肌修复。具体目标（SA）是： SA1：确定促进早期新生猪心脏细胞周期活动的关键调节因子 心肌损伤。我们将：1）使用最先进的分子生物学和成像技术，以及单一的 细胞/细胞核 RNA 测序（scRNAseq 或 snRNAseq）技术来证明这些关键 控制肌细胞周期的调节器/信号通路； 2) 测试受伤者的肌肉重建 通过使用靶向 modRNA 或 AAV9 选择性地修改这些关键调节因子来控制心室 AMI 成年猪的调节因子。 SA2a。工程 hCMP 具有以前无法达到的尺寸和厚度 功能成熟并为体内血管化做好准备。 SA2b。评估我们的有效性 hCMP 构建体用于大型动物（猪）心肌模型中的心肌恢复和再肌化 受伤。我们将结合使用最先进的光学测绘技术和 3 维 壁内心脏标测可描绘整个左心室的潜在心律失常机制 表面和透壁。

项目成果

Basic and Translational Research in Cardiac Repair and Regeneration: JACC State-of-the-Art Review.

• DOI: 10.1016/j.jacc.2021.09.019
• 发表时间: 2021-11-23
• 期刊: JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY
• 影响因子: 24
• 作者: Zhang, Jianyi;Bolli, Roberto;Garry, Daniel J.;Marban, Eduardo;Menasche, Philippe;Zimmermann, Wolfram-Hubertus;Kamp, Timothy J.;Wu, Joseph C.;Dzau, Victor J.
• 通讯作者: Dzau, Victor J.

Fabrication of a myocardial patch with cells differentiated from human-induced pluripotent stem cells.

• DOI: 10.1007/978-1-4939-2572-8_8
• 发表时间: 2015
• 期刊: Methods in molecular biology
• 作者: L. Ye;Joydeep Basu;Jianyi(Jay) Zhang

CCND2 Overexpression Enhances the Regenerative Potency of Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes: Remuscularization of Injured Ventricle.

• DOI: 10.1161/circresaha.117.311504
• 发表时间: 2018-01-05
• 期刊: Circulation research
• 影响因子: 20.1
• 作者: Zhu W;Zhao M;Mattapally S;Chen S;Zhang J
• 通讯作者: Zhang J

Analysis of cardiac single-cell RNA-sequencing data can be improved by the use of artificial-intelligence-based tools.

• DOI: 10.1038/s41598-023-32293-1
• 发表时间: 2023-04-26
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Nguyen T;Wei Y;Nakada Y;Chen JY;Zhou Y;Walcott G;Zhang J
• 通讯作者: Zhang J

Lactate Promotes Synthetic Phenotype in Vascular Smooth Muscle Cells.

• DOI: 10.1161/circresaha.117.311819
• 发表时间: 2017-11-10
• 期刊: Circulation research
• 影响因子: 20.1
• 作者: Yang L;Gao L;Nickel T;Yang J;Zhou J;Gilbertsen A;Geng Z;Johnson C;Young B;Henke C;Gourley GR;Zhang J
• 通讯作者: Zhang J