Maturation of Human Pluripotent Stem Cell-Derived Cardiomyocytes

人多能干细胞来源的心肌细胞的成熟

• 批准号: 10091506
• 负责人: Chunhui Xu
• 金额: $ 39万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-02-01 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10091506
• 关键词: 3-Dimensional; Address; Adverse event; Agonist; Arrhythmia; Biogenesis; Birth; Cardiac; Cardiac Myocytes; Cardiomyopathies; Cardiotoxicity; Cell Cycle; Cells; Chemicals; Clinical Research; Consumption; Cues; Data; Developmental Biology; Disease model; Down-Regulation; Drug usage; Fatty Acids; Gene Expression; Generations; Glucose; Glycolysis; Goals; Heart; Human; Human Development; In Vitro; Levocarnitine; Lipids; Mediating; Metabolic; Metabolism; Mitochondria; Molecular; Molecular Structure; Mutation; Neonatal; Newborn Infant; Oxygen; PPAR alpha; Pathway interactions; Pharmacology; Physiological; Play; Production; Publications; Regenerative Medicine; Regulation; Role; Signal Pathway; Signal Transduction; Source; Structure; Testing; Thyronines; Tissue Engineering; Transplantation; cardiac tissue engineering; cardiogenesis; drug discovery; experience; fatty acid oxidation; fetal; heart metabolism; human disease; human model; human pluripotent stem cell; improved; in vivo; induced pluripotent stem cell; inhibitor/antagonist; insight; metabolomics; novel; postnatal; preclinical study; response; sensor; stem cells; transcriptomics

MATURATION OF HUMAN PLURIPOTENT STEM CELL-DERIVED CARDIOMYOCYTES PROJECT SUMMARY Human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) provide a novel and physiologically relevant source of cells that have the potential to be used for in vitro cardiotoxicity testing and disease modeling as well as for the study of in vivo heart development and regenerative medicine. However, compared with primary human CMs, hPSC-CMs are structurally and functionally less mature, which limits their ability to accurately predict cardiotoxicity and model human development and diseases, and may result in adverse events such as arrhythmias upon transplantation. Therefore, improving hPSC-CM maturation is paramount in order to improve applications of these cells. We and other groups have previously demonstrated that efficient CM differentiation from hPSCs can be achieved via mimicking molecular signaling of cardiac induction during in vivo cardiogenesis. In our recent publications, we have also shown that microscale tissue engineering enables reliable generation of 3D cardiac spheres that contain highly enriched hPSC-CMs with enhanced sarcomeric structural maturation. We hypothesize that a multipronged, synergistic approach combining tissue engineering with modulation of multiple molecular signaling pathways can efficiently improve hPSC-CM maturation within short culture durations. With this hypothesis, we aim to enable metabolic and functional maturation of hPSC-CMs by providing the cells with (1) appropriate chemical signals to modulate metabolic maturation and (2) suitable environmental cues to mimic the transition from fetal CMs to postnatal CMs. We expect that this study will lead to the establishment of hPSC-CMs with cardiophysiology closer to human hearts, which will facilitate their applications in preclinical and clinical studies, and provide novel insights into molecular regulation of CM maturation.

人多能干细胞来源的心肌细胞的成熟 项目概要 人多能干细胞衍生的心肌细胞（hPSC-CM）提供了一种新颖且生理相关的 有潜力用于体外心脏毒性测试和疾病建模的细胞来源 至于体内心脏发育和再生医学的研究。但与初级相比 人类 CM、hPSC-CM 在结构和功能上尚不成熟，这限制了它们准确识别的能力 预测心脏毒性并模拟人类发育和疾病，并可能导致不良事件，例如 移植后出现心律失常。因此，为了提高 hPSC-CM 的成熟度，提高 hPSC-CM 的成熟度至关重要。 这些细胞的应用。我们和其他小组之前已经证明，有效的 CM 分化 从 hPSC 中提取可以通过模拟体内心脏发生过程中心脏诱导的分子信号传导来实现。 在我们最近的出版物中，我们还表明微型组织工程能够实现可靠的生成 含有高度富集的 hPSC-CM 的 3D 心脏球，具有增强的肌节结构成熟度。 我们假设将组织工程与调节相结合的多管齐下的协同方法 多种分子信号通路可有效促进短期培养内 hPSC-CM 的成熟 持续时间。有了这个假设，我们的目标是通过提供 hPSC-CM 的代谢和功能成熟 细胞具有（1）适当的化学信号来调节代谢成熟和（2）适当的环境 模拟从胎儿 CM 到产后 CM 转变的线索。我们期望这项研究将导致 建立心脏生理学更接近人类心脏的hPSC-CM，这将有利于其应用 临床前和临床研究，并为 CM 成熟的分子调控提供新的见解。

项目成果

A long non-coding RNA GATA6-AS1 adjacent to GATA6 is required for cardiomyocyte differentiation from human pluripotent stem cells.

与 GATA6 相邻的长非编码 RNA GATA6-AS1 是从人多能干细胞分化为心肌细胞所必需的。

• 发表时间: 2020
• 作者: Jha, Rajneesh;Li, Dong;Wu, Qingling;Ferguson, Katherine E;Forghani, Parvin;Gibson, Gregory C;Xu, Chunhui
• 通讯作者: Xu, Chunhui

Hypoplastic left heart syndrome: From bedside to bench and back.

• DOI: 10.1016/j.yjmcc.2019.08.005
• 发表时间: 2019-10-01
• 期刊: Journal of molecular and cellular cardiology
• 影响因子: 5
• 作者: Anita Saraf;W. Book;Timothy J. Nelson;Chunhui Xu
• 通讯作者: Chunhui Xu

Space microgravity improves proliferation of human iPSC-derived cardiomyocytes.

太空微重力可改善人类 iPSC 来源的心肌细胞的增殖。

• 发表时间: 2022-10-11
• 影响因子: 5.9
• 作者: Rampoldi, Antonio;Forghani, Parvin;Li, Dong;Hwang, Hyun;Armand, Lawrence Christian;Fite, Jordan;Boland, Gene;Maxwell, Joshua;Maher, Kevin;Xu, Chunhui
• 通讯作者: Xu, Chunhui

AMPK activator-treated human cardiac spheres enhance maturation and enable pathological modeling.

经过 AMPK 激活剂处理的人类心脏球体可促进成熟并实现病理建模。

• 发表时间: 2023-11-08
• 影响因子: 7.5
• 作者: Li, Dong;Armand, Lawrence C;Sun, Fangxu;Hwang, Hyun;Wolfson, David;Rampoldi, Antonio;Liu, Rui;Forghani, Parvin;Hu, Xin;Yu, Wen;Qu, Cheng;Jones, Dean P;Wu, Ronghu;Cho, Hee Cheol;Maxwell, Joshua T;Xu, Chunhui
• 通讯作者: Xu, Chunhui

Simulated microgravity improves maturation of cardiomyocytes derived from human induced pluripotent stem cells.

模拟微重力可促进源自人类诱导多能干细胞的心肌细胞的成熟。

• 发表时间: 2024-01-26
• 影响因子: 4.6
• 作者: Forghani, Parvin;Rashid, Aysha;Armand, Lawrence C;Wolfson, David;Liu, Rui;Cho, Hee Cheol;Maxwell, Joshua T;Jo, Hanjoong;Salaita, Khalid;Xu, Chunhui
• 通讯作者: Xu, Chunhui