Human Pluripotent Stem Cell-Derived Cardiac Tissue-like Constructs for Repairing the Infarcted Myocardium

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Human Pluripotent Stem Cell-Derived Cardiac Tissue-like Constructs for Repairing the Infarcted Myocardium, Stem Cell Reports, 2017, 9, 1546–1559

 

Human pluripotent stem cells (hPSCs), including human embryonic stem cells (hESCs) and human induced pluripotent stem cells (hiPSCs), can be differentiated into cardiomyocytes (hPSC-CMs), which offer a number of advantages for drug development as well as for myocardial regeneration. However, although high-purity CM differentiation can be achieved, the hPSC-CMs derived under normal conditions are randomly distributed and resemble immature rather than adult CMs, as demonstrated by their morphological and functional characteristics. Accordingly, the reported 2D culture should not be used for high-performance drug screening. More recent studies have been based on 3D CM tissue construction, showing improved maturation with respect to the 2D control. In parallel, myocardial regeneration for repairing injured heart has progressed by using cell injections, cell sheets, or cell patches. However, the above in vivo studies were mostly based on poorly organized hPSC-CMs, and only a few recent investigations have paid attention to the 3D cellular organization in engineered tissues, showing a longerterm survival and improved ventricular functions after tissue engraftment.

 

To reproduce the in vivo cardiac tissue organization, nanofibers with high surface area to volume ratios were used for cardiac tissue engineering. CMs on the aligned nanofibers can form, for example, cell-elongated tissue-like constructs with enhanced maturation and improved ability to repair myocardial infarction (MI). Critical issues such as limited cell infiltration in the nanofiber systems, fiber layer thickness, fiber degradability, and fiber stiffness remain to be addressed since they are important for the implantation and treatment of sustained re-entrant arrhythmias after transplantation.

 

 

In conclusion, we created organized and functional CTLCs. Multilayered elongated CMs within the constructs showed upregulated gene expression of cardiac markers, enhanced extracellular recording, and robust drug response. When used for engraftment, CTLCs demonstrated excellent operability while enabling rapid coupling and suppression of re-entrant arrhythmia in disconnected or scarred tissue blocks.We also demonstrated post-surgery cell survival in CTLCs and their ability to repair MI in a rat model. Overall, the CTLCs have great potential for future use in cell-based applications, including drug testing and regenerative cardiac therapy.

 

Pour plus d'information, consultez le communiqué de presse associé à cet article : Réparer le cœur après un infarctus à l’aide de cellules souches !

 

Résumé: 

Stem Cell Reports, 2017, 9, 1546–1559

 

High-purity cardiomyocytes (CMs) derived from human induced pluripotent stem cells (hiPSCs) are promising for drug development and myocardial regeneration. However, most hiPSC-derived CMs morphologically and functionally resemble immature rather than adult CMs, which could hamper their application. Here, we obtained high-quality cardiac tissue-like constructs (CTLCs) by cultivating hiPSC-CMs on low-thickness aligned nanofibers made of biodegradable poly(D,L-lactic-co-glycolic acid) polymer. We show that multilayered and elongated CMs could be organized at high density along aligned nanofibers in a simple one-step seeding process, resulting in upregulated cardiac biomarkers and enhanced cardiac functions. When used for drug assessment, CTLCs were much more robust than the 2D conventional control.We also demonstrated the potential of CTLCs for modeling engraftments in vitro and treating myocardial infarction in vivo. Thus, we established a handy framework for cardiac tissue engineering, which holds high potential for pharmaceutical and clinical applications.

 

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Human Pluripotent Stem Cell-Derived Cardiac Tissue-like Constructs for Repairing the Infarcted Myocardium

 

Junjun Li, Itsunari Minami, Motoko Shiozaki, Leqian Yu, Shin Yajima, Shigeru Miyagawa, Yuji Shiba, Nobuhiro Morone, Satsuki Fukushima, Momoko Yoshioka, Sisi Li, Jing Qiao, Xin Li, Lin Wang, Hidetoshi Kotera, Norio Nakatsuji, Yoshiki Sawa, Yong Chen, and Li Liu

 

Stem Cell Reports, 2017, 9, 1546–1559

 

DOI : 10.1016/j.stemcr.2017.09.007