Marchianò Silvia, Bertero Alessandro, Murry Charles E
Department of Pathology, University of Washington, 1959 NE Pacific Street, Seattle, WA, 98195, USA.
Center for Cardiovascular Biology, University of Washington, 850 Republican Street, Brotman Building, Seattle, WA, 98109, USA.
Pediatr Cardiol. 2019 Oct;40(7):1367-1387. doi: 10.1007/s00246-019-02165-5. Epub 2019 Aug 6.
Human pluripotent stem cells (hPSCs) offer a multifaceted platform to study cardiac developmental biology, understand disease mechanisms, and develop novel therapies. Remarkable progress over the last two decades has led to methods to obtain highly pure hPSC-derived cardiomyocytes (hPSC-CMs) with reasonable ease and scalability. Nevertheless, a major bottleneck for the translational application of hPSC-CMs is their immature phenotype, resembling that of early fetal cardiomyocytes. Overall, bona fide maturation of hPSC-CMs represents one of the most significant goals facing the field today. Developmental biology studies have been pivotal in understanding the mechanisms to differentiate hPSC-CMs. Similarly, evaluation of developmental cues such as electrical and mechanical activities or neurohormonal and metabolic stimulations revealed the importance of these pathways in cardiomyocyte physiological maturation. Those signals cooperate and dictate the size and the performance of the developing heart. Likewise, this orchestra of stimuli is important in promoting hPSC-CM maturation, as demonstrated by current in vitro maturation approaches. Different shades of adult-like phenotype are achieved by prolonging the time in culture, electromechanical stimulation, patterned substrates, microRNA manipulation, neurohormonal or metabolic stimulation, and generation of human-engineered heart tissue (hEHT). However, mirroring this extremely dynamic environment is challenging, and reproducibility and scalability of these approaches represent the major obstacles for an efficient production of mature hPSC-CMs. For this reason, understanding the pattern behind the mechanisms elicited during the late gestational and early postnatal stages not only will provide new insights into postnatal development but also potentially offer new scalable and efficient approaches to mature hPSC-CMs.
人类多能干细胞（hPSC）为研究心脏发育生物学、理解疾病机制以及开发新疗法提供了一个多方面的平台。在过去二十年中取得的显著进展已带来了一些方法，能够相对轻松且可扩展地获得高度纯净的源自hPSC的心肌细胞（hPSC-CM）。然而，hPSC-CM转化应用的一个主要瓶颈是它们的不成熟表型，类似于早期胎儿心肌细胞的表型。总体而言，hPSC-CM的真正成熟是当今该领域面临的最重要目标之一。发育生物学研究对于理解hPSC-CM的分化机制至关重要。同样，对电活动和机械活动或神经激素和代谢刺激等发育线索的评估揭示了这些途径在心肌细胞生理成熟中的重要性。这些信号相互协作并决定发育中心脏的大小和性能。同样，正如当前的体外成熟方法所表明的，这种刺激的协同作用对于促进hPSC-CM的成熟也很重要。通过延长培养时间、机电刺激、图案化基质、微小RNA操纵、神经激素或代谢刺激以及构建人源工程心脏组织（hEHT），可以实现不同程度的类似成体的表型。然而，模拟这种极其动态的环境具有挑战性，并且这些方法的可重复性和可扩展性是高效生产成熟hPSC-CM的主要障碍。因此，了解妊娠晚期和出生后早期阶段引发的机制背后的模式，不仅将为出生后发育提供新的见解，还可能为成熟hPSC-CM提供新的可扩展且高效的方法。
