Engineered Human Heart Slice for Testing Drug-Induced Arrhythmia

家长基金“用于测试药物引起的心律失常的工程人体心脏切片”旨在 开发一种工程化的心跳切片(EHS)模型，它将能够测试药物诱导的、 快速性心律失常。EHS模型中的心肌细胞取自人 诱导多能干细胞来源的心肌细胞(hiPSC-CMS)。而HiPSC-CMS是一种 这些细胞有希望成为心肌细胞的来源，但它们的成熟状态有限。HiPSC- CMS目前在发育过程中像胎儿一样，需要兴奋剂才能达到成人型 表型。父母资助的重点是机电、生物和成熟技术的使用 在HiPSC-CMS中获得这种表型的媒介。这就引出了本补充文章的目标 研究，这是应用一种替代刺激剂，以帮助HiPSC-CMS成熟。这 刺激剂是脂肪细胞(脂肪生成细胞)的分泌体。脂肪细胞将作为一个 脂肪酸的来源，已被证明在代谢成熟中有影响 心肌细胞。这项补充工作的具体目的是调查有益的(或 人类脂肪干细胞分泌体的病理作用 作为HiPSC-CMS成熟刺激剂的细胞(HASCs)未经处理，分选CD36+ (代谢成熟标记物)，或源自被诊断为致心律失常的患者 室性心肌病。补充研究还将检查这些反应是否 的HiPSC-CMS在由脱细胞心脏组成的更3D的环境中增强 组织。

The parent grant “Engineered Human Heart Slice for Testing Drug-Induced Arrhythmia” aims to develop an engineered hear slice (EHS) model that will have the ability to test for drug-induced, cardiac tachyarrhythmias. The cardiomyocytes in the EHS model are obtained from human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). While hiPSC-CMs are a promising cell source for cardiomyocytes, these cells are limited in their maturation state. hiPSC- CMs are currently fetal-like in their development, and require stimulants to achieve an adult-like phenotype. The parent grant focuses on the use of electromechanical, biological, and maturation medias to attain such a phenotype in hiPSC-CMs. This leads to the goal of this supplemental research, which is to apply an alternate stimulant to aid in the maturation of hiPSC-CMs. This stimulant is the secretome from adipocytes (fat generating cells). The adipocytes will serve as a source of fatty acids, which have proven to be influential in the metabolic maturation of cardiomyocytes. The specific aim of this supplemental work is to investigate the beneficial (or pathological) role of the secretome from adipocytes derived from human Adipose-Derived Stem Cells (hASCs) as a maturation stimulant for hiPSC-CMs that are either untreated, sorted for CD36+ (a metabolic maturation marker), or derived from patients diagnosed with arrhythmogenic right ventricular cardiomyopathy. The supplemental research will also examine whether the responses of the hiPSC-CMs are enhanced in a more 3D environment consisting of decellularized cardiac tissue.