基于FUCCI的实时成像平台揭示了人诱导多能干细胞衍生心肌细胞的细胞周期动态并鉴定出促增殖化合物。
FUCCI-Based Live Imaging Platform Reveals Cell Cycle Dynamics and Identifies Pro-proliferative Compounds in Human iPSC-Derived Cardiomyocytes.
作者信息
Murganti Francesca, Derks Wouter, Baniol Marion, Simonova Irina, Trus Palina, Neumann Katrin, Khattak Shahryar, Guan Kaomei, Bergmann Olaf
机构信息
Center for Regenerative Therapies Dresden, TU Dresden, Dresden, Germany.
Karolinska Institute, Cell and Molecular Biology (CMB), Stockholm, Sweden.
出版信息
Front Cardiovasc Med. 2022 Apr 25;9:840147. doi: 10.3389/fcvm.2022.840147. eCollection 2022.
One of the major goals in cardiac regeneration research is to replace lost ventricular tissue with new cardiomyocytes. However, cardiomyocyte proliferation drops to low levels in neonatal hearts and is no longer efficient in compensating for the loss of functional myocardium in heart disease. We generated a human induced pluripotent stem cell (iPSC)-derived cardiomyocyte-specific cell cycle indicator system (TNNT2-FUCCI) to characterize regular and aberrant cardiomyocyte cycle dynamics. We visualized cell cycle progression in TNNT2-FUCCI and found G2 cycle arrest in endoreplicating cardiomyocytes. Moreover, we devised a live-cell compound screening platform to identify pro-proliferative drug candidates. We found that the alpha-adrenergic receptor agonist clonidine induced cardiomyocyte proliferation and increased cardiomyocyte cell cycle entry in neonatal mice. In conclusion, the TNNT2-FUCCI system is a versatile tool to characterize cardiomyocyte cell cycle dynamics and identify pro-proliferative candidates with regenerative potential in the mammalian heart.
心脏再生研究的主要目标之一是用新的心肌细胞替代丢失的心室组织。然而，心肌细胞增殖在新生儿心脏中降至低水平，并且在心脏病中不再能够有效地补偿功能性心肌的损失。我们生成了一种源自人诱导多能干细胞（iPSC）的心肌细胞特异性细胞周期指示系统（TNNT2-FUCCI），以表征正常和异常的心肌细胞周期动态。我们观察了TNNT2-FUCCI中的细胞周期进程，发现终末复制心肌细胞中存在G2期阻滞。此外，我们设计了一个活细胞化合物筛选平台，以鉴定促增殖药物候选物。我们发现α-肾上腺素能受体激动剂可乐定可诱导新生小鼠心肌细胞增殖并增加心肌细胞进入细胞周期的比例。总之，TNNT2-FUCCI系统是一种多功能工具，可用于表征心肌细胞周期动态，并鉴定在哺乳动物心脏中具有再生潜力的促增殖候选物。
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