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）：心脏病是美国每年男女死亡的头号原因。尽管近年来在常规药物和器械治疗方面取得了重大进展，但它们还不能逆转功能性心肌的丧失。有一天，通过从人类干细胞中获得功能性心肌细胞，心脏再生可能成为可能。然而，在将这些细胞用于心脏修复之前，必须对它们的电生理以及它们与天然心脏组织无缝整合的可能性有更多的了解。特别是，建立这些细胞与宿主心肌的电生理相容性对于降低心律失常的风险至关重要。尽管有这一关键需求，但迄今为止所研究的所有细胞类型的电生理表型分类在很大程度上是主观的，主要依赖于与动作电位形状相关的参数。该项目的总体目标是基于机器学习开发的技术，开发一种新的，分析和自动化的方法来分类新分化的心脏细胞。具体目标是，首先，使用光学测绘和微电极记录来生成人类胚胎干细胞来源的心肌细胞（hESC-CMs）的功能电生理特征数据集，其次，使用机器学习技术根据参数描述对hESC-CMs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。不同分化阶段的细胞将在不同的起搏和药理学条件下进行评估，这将有助于建立细胞的功能特性。总之，提出的研究将使从人类干细胞衍生的心肌细胞的分类成为可能。分类和识别心肌细胞表型的能力将允许定量评估细胞培养中批对批的可变性，不同分化过程的影响，以及心肌细胞分化和成熟过程中表型的演变。这些都是未来这些细胞在心脏组织再生中的临床应用至关重要的问题。