Perspective on human pluripotent stem cell-derived cardiomyocytes in heart disease modeling and repair

Li, Qiang; Wang, Jia; Wu, Qiang; Cao, Nan; Yang, Huang‐Tian

doi:10.1002/sctm.19-0340

Cited by 18 publications

(11 citation statements)

References 80 publications

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“…It is worthy further study to thoroughly identify potentially secreted‐proteins from hCVPCs which contribute to cardioprotection. These findings, together with the observations of the cardiac benefits from various cell‐based therapies when delivered during the early phase of I/R or MI, 7,8,15 suggest that the paracrine effects are a critical mechanism in cell‐based therapies for myocardial I/R via triggering of endogenous cardioprotective and repair programs 52,53 . Thus, further characterization of the stem cell secretome and identification of specific paracrine factors would provide an opportunity to develop protein therapeutics that protect and repair damaged hearts.…”

Section: Discussionmentioning

confidence: 99%

Neurotrophin-3 contributes to benefits of human embryonic stem cell-derived cardiovascular progenitor cells against reperfused myocardial infarction

Wang

Jiang

et al. 2021

Stem Cells Translational Medicine

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Acute myocardial infarction (MI) resulting from coronary ischemia is a major cause of disability and death worldwide. Transplantation of human embryonic stem cell (hESC)‐derived cardiovascular progenitor cells (hCVPCs) promotes the healing of infarcted hearts by secreted factors. However, the hCVPC‐secreted proteins contributing to cardiac repair remain largely unidentified. In this study, we investigated protective effects of neurotrophin (NT)‐3 secreted from hCVPCs in hearts against myocardial ischemia/reperfusion (I/R) injury and explored the underlying mechanisms to determine the potential of using hCVPC products as a new therapeutic strategy. The implantation of hCVPCs into infarcted myocardium at the beginning of reperfusion following 1 hour of ischemia improved cardiac function and scar formation of mouse hearts. These beneficial effects were concomitant with reduced cardiomyocyte death and increased angiogenesis. Moreover, hCVPCs secreted a rich abundance of NT‐3. The cardioreparative effect of hCVPCs in the I/R hearts was mimicked by human recombinant NT‐3 (hNT‐3) but canceled by NT‐3 neutralizing antibody (NT‐3‐Ab). Furthermore, endogenous NT‐3 was detected in mouse adult cardiomyocytes and its level was enhanced in I/R hearts. Adenovirus‐mediated NT‐3 knockdown exacerbated myocardial I/R injury. Mechanistically, hNT‐3 and endogenous NT‐3 inhibited I/R‐induced cardiomyocyte apoptosis through activating the extracellular signal‐regulated kinase (ERK) and reducing the Bim level, resulting in the cardioreparative effects of infarcted hearts together with their effects in the improvement of angiogenesis. These results demonstrate for the first time that NT‐3 is a cardioprotective factor secreted by hCVPCs and exists in adult cardiomyocytes that reduces I/R‐induced cardiomyocyte apoptosis via the ERK‐Bim signaling pathway and promotes angiogenesis. As a cell product, NT‐3 may represent as a noncell approach for the treatment of myocardial I/R injury.

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Section: Discussionmentioning

confidence: 99%

Neurotrophin-3 contributes to benefits of human embryonic stem cell-derived cardiovascular progenitor cells against reperfused myocardial infarction

Wang

Jiang

et al. 2021

Stem Cells Translational Medicine

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“…Immature phenotype, discussed in more details later, is a crucial disadvantage of hiPSC-CMs, affecting their structural, electrophysiological, and metabolic characteristic (reviewed by Yang et al [ 193 ] and Karbassi et al [ 85 ]) and have led to the development of procedures enabling enhancement of maturation, such as long-term culture [ 82 , 94 ], electrical stimulation [ 95 , 133 , 156 ] or more recent maturation media with fatty acid supplementation [ 54 , 72 ], application of small molecules [ 110 ] and identification of cell surface markers [ 142 ]. For detailed reviews on this topic, see Zhao et al 2020, Karbassi et al 2020 and Li et al 2020 [ 85 , 103 , 203 ].…”

Section: Hipsc-derived Cardiomyocytes Application For Drug Researchmentioning

confidence: 99%

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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“…Furthermore, the modulation of cardiac function via drugs targeting the cANS can be advantageous regarding drug development for cardiovascular diseases [ 5 ]. For example, therapeutic targeting of neurons to improve cardiac outcome after heart failure is important; however, studying this requires human cell-based models as drug responses and disease mechanisms between animal and human cells can be different [ 3 , 6 , 7 ]. Moreover, detection of adverse effects in cardiac tissue or the cANS is important to ensure drug safety [ 3 ].…”

Section: Introductionmentioning

confidence: 99%

Human Neurons Form Axon-Mediated Functional Connections with Human Cardiomyocytes in Compartmentalized Microfluidic Chip

Häkli

Jäntti

Joki

et al. 2022

IJMS

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The cardiac autonomic nervous system (cANS) regulates cardiac function by innervating cardiac tissue with axons, and cardiomyocytes (CMs) and neurons undergo comaturation during the heart innervation in embryogenesis. As cANS is essential for cardiac function, its dysfunctions might be fatal; therefore, cardiac innervation models for studying embryogenesis, cardiac diseases, and drug screening are needed. However, previously reported neuron-cardiomyocyte (CM) coculture chips lack studies of functional neuron–CM interactions with completely human-based cell models. Here, we present a novel completely human cell-based and electrophysiologically functional cardiac innervation on a chip in which a compartmentalized microfluidic device, a 3D3C chip, was used to coculture human induced pluripotent stem cell (hiPSC)-derived neurons and CMs. The 3D3C chip enabled the coculture of both cell types with their respective culture media in their own compartments while allowing the neuronal axons to traverse between the compartments via microtunnels connecting the compartments. Furthermore, the 3D3C chip allowed the use of diverse analysis methods, including immunocytochemistry, RT-qPCR and video microscopy. This system resembled the in vivo axon-mediated neuron–CM interaction. In this study, the evaluation of the CM beating response during chemical stimulation of neurons showed that hiPSC-neurons and hiPSC-CMs formed electrophysiologically functional axon-mediated interactions.

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Perspective on human pluripotent stem cell-derived cardiomyocytes in heart disease modeling and repair

Cited by 18 publications

References 80 publications

Neurotrophin-3 contributes to benefits of human embryonic stem cell-derived cardiovascular progenitor cells against reperfused myocardial infarction

Neurotrophin-3 contributes to benefits of human embryonic stem cell-derived cardiovascular progenitor cells against reperfused myocardial infarction

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

Human Neurons Form Axon-Mediated Functional Connections with Human Cardiomyocytes in Compartmentalized Microfluidic Chip

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