Functional Classification of Cardiomyocytes Derived from Stem Cells

干细胞来源的心肌细胞的功能分类

• 批准号: 8095482
• 负责人: LESLIE TUNG
• 金额: $ 24.6万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-20 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8095482
• 关键词: Action Potentials; Address; Adipocytes; Adrenergic Agents; Algorithms; Arrhythmia; Blood Cells; Bone Marrow; Cardiac; Cardiac Myocytes; Cause of Death; Cell Culture Techniques; Cells; Characteristics; Classification; Data; Data Set; Descriptor; Development; Devices; Discriminant Analysis; Electrophysiology (science); Embryo; Evaluation; Evolution; Face; Frequencies; Future; Goals; Heart; Heart Atrium; Heart Diseases; Isometric Exercise; Machine Learning; Maps; Measurement; Methods; Microelectrodes; Morphology; Myocardium; Natural regeneration; Nodal; Optics; Pharmaceutical Preparations; Phenotype; Principal Component Analysis; Procedures; Property; Regenerative Medicine; Research; Research Personnel; Resources; Rest; Risk; Series; Shapes; Staging; Stem cells; Techniques; Testing; Time; Tissues; Training; Transplantation; Umbilical Cord Blood; United States; Variant; Ventricular; Woman; Wound Healing; adrenergic; adult stem cell; base; cell type; cholinergic; clinical application; functional loss; heart cell; human embryonic stem cell; human stem cells; induced pluripotent stem cell; innovation; interest; men; molecular marker; novel; repaired; research study; response; stem cell therapy

DESCRIPTION (provided by applicant): Heart disease is the number one cause of death in the United States each year for both women and men. Although significant advances have been made in conventional drug and device therapies in recent years, they have not been able to reverse the loss of functional myocardium. Regeneration of the heart may someday be possible with the ability to derive functional cardiomyocytes from human stem cells. However, before these cells can be used for cardiac repair, more must be known about their electrophysiology and their likelihood to seamlessly integrate with native cardiac tissue. In particular, it is of critical importance to establish the electrophysiological compatibility of these cells with host myocardium to minimize the risk of arrhythmia. Despite this critical need, the classification of the electrophysiological phenotypes has been largely subjective for all cell types that have been studied so far, relying mainly on parameters related to action potential shape. The overall goal of this project is to develop a new, analytical and automated method to classify newly differentiated cardiac cells, based on techniques developed for machine learning. The specific aims are first, to use optical mapping and microelectrode recordings to generate datasets of functional electrophysiological characteristics of human embryonic stem cell-derived cardiomyocytes (hESC-CMs), and second, to use machine learning techniques to classify the phenotypes of the hESC-CMs, based on parametric descriptions. These techniques will involve linear and nonlinear dimensionality reduction algorithms, and clustering and classification algorithms. Cells at different stages of differentiation will be evaluated at different pacing and pharmacological conditions that will help to establish the functional properties of the cells. In summary, the proposed research will enable the classification of cardiomyocytes that are derived from human stem cells. The ability to classify and identify cardiomyocyte phenotypes will permit a quantitative assessment of the batch-to-batch variability in cell cultures, the effect of different differentiation procedures, and the evolution of phenotypes during cardiomyocyte differentiation and maturation. These are critically important issues for the future clinical application of these cells to regenerate cardiac tissue. PUBLIC HEALTH RELEVANCE: Stem cell therapy holds great potential for treating diseased and failing hearts, but still faces significant challenges. This project addresses the electrophysiological aspects these cells, and the goal is to develop methods that can classify and identify the variety of heart cells that are derived from different kinds of stem cells.

描述（由申请人提供）：心脏病是美国每年女性和男性的头号死因。尽管近年来在常规药物和器械治疗方面取得了显著进展，但它们无法逆转功能性心肌的丧失。有朝一日，心脏的再生可能会从人类干细胞中获得功能性心肌细胞。然而，在这些细胞可用于心脏修复之前，必须更多地了解它们的电生理学及其与天然心脏组织无缝整合的可能性。特别是，建立这些细胞与宿主心肌的电生理相容性以使心律失常的风险最小化是至关重要的。尽管有这种关键的需求，电生理表型的分类一直在很大程度上是主观的所有细胞类型，迄今为止已经研究，主要依赖于动作电位形状相关的参数。 该项目的总体目标是开发一种新的分析和自动化方法，基于机器学习技术对新分化的心脏细胞进行分类。具体目标是，首先，使用光学映射和微电极记录来生成人胚胎干细胞衍生的心肌细胞（hESC-CM）的功能电生理特征的数据集，其次，基于参数描述，使用机器学习技术来对hESC-CM的表型进行分类。这些技术将涉及线性和非线性降维算法以及聚类和分类算法。将在不同的起搏和药理学条件下评估处于不同分化阶段的细胞，这将有助于建立细胞的功能特性。 总之，拟议的研究将使来自人类干细胞的心肌细胞的分类成为可能。分类和鉴定心肌细胞表型的能力将允许定量评估细胞培养物中批次间的变异性、不同分化程序的影响以及心肌细胞分化和成熟期间表型的演变。这些对于这些细胞再生心脏组织的未来临床应用至关重要。 公共卫生相关性：干细胞疗法在治疗心脏疾病和衰竭方面具有巨大潜力，但仍面临重大挑战。该项目涉及这些细胞的电生理方面，目标是开发可以分类和识别来自不同种类干细胞的各种心脏细胞的方法。