PGC-1α activator ZLN005 promotes maturation of cardiomyocytes derived from human embryonic stem cells

Liu, Yanping; Bai, Hua-Jun; Guo, Fan; Thai, Phung N.; Luo, Xiaoling; Zhang, Peng; Yang, Cui; Feng, Xueqin; Zhu, Dan; Guo, Jun; Liang, Ping; Yang, Huang‐Tian; Lu, Xiyuan

doi:10.18632/aging.103088

Cited by 27 publications

(25 citation statements)

References 73 publications

(118 reference statements)

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“…In our study, APD 50 was significantly prolonged in the RA-treated hESC-CMs (395.8 ± 47.7 ms in the RA group versus 280.4 ± 30.2 ms in the DMSO group, p <0.05), and APD 90 showed the similar trend after RA treatment (491.1 ± 54.3 ms in the RA group versus 337.0 ± 30.6 ms in the DMSO group, p <0.05) (Figure 6 A-C). These results were consistent with previous reports 6 , 39 , 40 , implying RA promoted cardiomyocyte electrophysiological maturity.…”

Section: Resultssupporting

confidence: 94%

“…The amplitude of Ca 2+ transient was unchanged by RA treatment (Figure 6 G). Consistent with previous reports 9 , 10 , 40 , these results indicate RA treatment promotes hESC-CM functional maturation, in term of electrophysiology and calcium handling.…”

Section: Resultssupporting

confidence: 93%

“…To further verify the functional maturity of the hESC-CMs at an electrophysiological level, action potential was measured with patch clamp technique. The action potential duration at 50% repolarization (APD 50 ) and APD 90 were usually used to verify the maturity of cardiomyocytes 6 , 39 , 40 . In our study, APD 50 was significantly prolonged in the RA-treated hESC-CMs (395.8 ± 47.7 ms in the RA group versus 280.4 ± 30.2 ms in the DMSO group, p <0.05), and APD 90 showed the similar trend after RA treatment (491.1 ± 54.3 ms in the RA group versus 337.0 ± 30.6 ms in the DMSO group, p <0.05) (Figure 6 A-C).…”

Section: Resultsmentioning

confidence: 99%

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Retinoic acid promotes metabolic maturation of human Embryonic Stem Cell-derived Cardiomyocytes

Miao¹,

Zhao²,

Wang

et al. 2020

Theranostics

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Cardiomyocytes differentiated from human embryonic stem cells (hESCs) represent a promising cell source for heart repair, disease modeling and drug testing. However, improving the differentiation efficiency and maturation of hESC-derived cardiomyocytes (hESC-CMs) is still a major concern. Retinoic acid (RA) signaling plays multiple roles in heart development. However, the effects of RA on cardiomyocyte differentiation efficiency and maturation are still unknown. Methods: RA was added at different time intervals to identify the best treatment windows for cardiomyocyte differentiation and maturation. The efficiency of cardiomyocyte differentiation was detected by quantitative real-time PCR and flow cytometry. Cardiomyocytes maturation was detected by immunofluorescence staining, metabolic assays and patch clamp to verify structural, metabolic and electrophysiological maturation, respectively. RNA sequencing was used for splicing analysis. Results: We found that RA treatment at the lateral mesoderm stage (days 2-4) significantly improved cardiomyocyte differentiation, as evidenced by the upregulation of TNNT2 , NKX2.5 and MYH6 on day 10 of differentiation. In addition, flow cytometry showed that the proportion of differentiated cardiomyocytes in the RA-treated group was significantly higher than that in control group. RA treatment on days 15-20 increased cardiomyocyte area, sarcomere length, multinucleation and mitochondrial copy number. RNA sequencing revealed RA promoted RNA isoform switch to the maturation-related form. Meanwhile, RA promoted electrophysiological maturation and calcium handling of hESC-CMs. Importantly, RA-treated cardiomyocytes showed decreased glycolysis and enhanced mitochondrial oxidative phosphorylation, with the increased utilization of fatty acid and exogenous pyruvate but not glutamine. Conclusion: Our data indicated that RA treatment at an early time window (days 2-4) promotes the efficiency of cardiomyocyte differentiation and that RA treatment post beating (days 15-20) promotes cardiomyocyte maturation. The biphasic effects of RA provide new insights for improving cardiomyocyte differentiation and quality.

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Section: Resultssupporting

confidence: 94%

Section: Resultssupporting

confidence: 93%

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Retinoic acid promotes metabolic maturation of human Embryonic Stem Cell-derived Cardiomyocytes

Miao¹,

Zhao²,

Wang

et al. 2020

Theranostics

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“…The mechanism by which dexamethasone acts may be through mitochondrial maturation. Activation of the glucocorticoid receptor upregulates expression of PPARγ (peroxisome proliferator-activated receptor γ) coactivator 1α (PGC-1α) [88], a transcriptional coactivator that induces mitochondrial biogenesis and maturation [89]. Furthermore, short-term (24 h) dexamethasone treatment promotes maturation and inhibits proliferation of mouse ESC-CMs via mitochondrial aggregation of LC3 and induction of Parkin-mediated mitophagy [90].…”

Section: Glucocorticoidsmentioning

confidence: 99%

“…PSC-CMs upregulate PGC-1α during differentiation [155]. Activation of PGC-1α with ZLN005 improves maturation of PSC-CMs [89], while overexpression of PGC-1α in H9c2 cells stimulates mitochondrial biogenesis and autophagy to protect against lipopolysaccharide-induced apoptosis [156]. Contractile work requires increased ATP levels and this may also trigger enhanced mitochondrial biogenesis [157].…”

Section: Mitochondrial Biogenesismentioning

confidence: 99%

Mitochondria and metabolic transitions in cardiomyocytes: lessons from development for stem cell-derived cardiomyocytes

Garbern

Lee

2021

Stem Cell Res Ther

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Current methods to differentiate cardiomyocytes from human pluripotent stem cells (PSCs) inadequately recapitulate complete development and result in PSC-derived cardiomyocytes (PSC-CMs) with an immature or fetal-like phenotype. Embryonic and fetal development are highly dynamic periods during which the developing embryo or fetus is exposed to changing nutrient, oxygen, and hormone levels until birth. It is becoming increasingly apparent that these metabolic changes initiate developmental processes to mature cardiomyocytes. Mitochondria are central to these changes, responding to these metabolic changes and transitioning from small, fragmented mitochondria to large organelles capable of producing enough ATP to support the contractile function of the heart. These changes in mitochondria may not simply be a response to cardiomyocyte maturation; the metabolic signals that occur throughout development may actually be central to the maturation process in cardiomyocytes. Here, we review methods to enhance maturation of PSC-CMs and highlight evidence from development indicating the key roles that mitochondria play during cardiomyocyte maturation. We evaluate metabolic transitions that occur during development and how these affect molecular nutrient sensors, discuss how regulation of nutrient sensing pathways affect mitochondrial dynamics and function, and explore how changes in mitochondrial function can affect metabolite production, the cell cycle, and epigenetics to influence maturation of cardiomyocytes.

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Human-induced pluripotent stem cell-derived cardiomyocytes, 3D cardiac structures, and heart-on-a-chip as tools for drug research

Andrysiak

Stępniewski

Dulak

2021

Pflugers Arch - Eur J Physiol

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Development of new drugs is of high interest for the field of cardiac and cardiovascular diseases, which are a dominant cause of death worldwide. Before being allowed to be used and distributed, every new potentially therapeutic compound must be strictly validated during preclinical and clinical trials. The preclinical studies usually involve the in vitro and in vivo evaluation. Due to the increasing reporting of discrepancy in drug effects in animal and humans and the requirement to reduce the number of animals used in research, improvement of in vitro models based on human cells is indispensable. Primary cardiac cells are difficult to access and maintain in cell culture for extensive experiments; therefore, the human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) became an excellent alternative. This technology enables a production of high number of patient- and disease-specific cardiomyocytes and other cardiac cell types for a large-scale research. The drug effects can be extensively evaluated in the context of electrophysiological responses with a use of well-established tools, such as multielectrode array (MEA), patch clamp, or calcium ion oscillation measurements. Cardiotoxicity, which is a common reason for withdrawing drugs from marketing or rejection at final stages of clinical trials, can be easily verified with a use of hiPSC-CM model providing a prediction of human-specific responses and higher safety of clinical trials involving patient cohort. Abovementioned studies can be performed using two-dimensional cell culture providing a high-throughput and relatively lower costs. On the other hand, more complex structures, such as engineered heart tissue, organoids, or spheroids, frequently applied as co-culture systems, represent more physiological conditions and higher maturation rate of hiPSC-derived cells. Furthermore, heart-on-a-chip technology has recently become an increasingly popular tool, as it implements controllable culture conditions, application of various stimulations and continuous parameters read-out. This paper is an overview of possible use of cardiomyocytes and other cardiac cell types derived from hiPSC as in vitro models of heart in drug research area prepared on the basis of latest scientific reports and providing thorough discussion regarding their advantages and limitations.

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PGC-1α activator ZLN005 promotes maturation of cardiomyocytes derived from human embryonic stem cells

Cited by 27 publications

References 73 publications

Retinoic acid promotes metabolic maturation of human Embryonic Stem Cell-derived Cardiomyocytes

Retinoic acid promotes metabolic maturation of human Embryonic Stem Cell-derived Cardiomyocytes

Mitochondria and metabolic transitions in cardiomyocytes: lessons from development for stem cell-derived cardiomyocytes

Human-induced pluripotent stem cell-derived cardiomyocytes, 3D cardiac structures, and heart-on-a-chip as tools for drug research

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