Human induced pluripotent stem cell-derived cardiac myocytes and sympathetic neurons in disease modelling

Li, Ni; Edel, Michael J.; Liu, Kun; Denning, Chris; Betts, Jacob; Neely, Oliver C.; Li, Dan; Paterson, David J.

doi:10.1098/rstb.2022.0173

Cited by 8 publications

(3 citation statements)

References 50 publications

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“…Nevertheless, recent reports describe hiPSC-CMs with atrial AP properties and acetylcholine-activated K + current expression ( Ahmad et al, 2023 ). There are recent iPSC models for normal and disease changes in ion channel expression, Ca 2+ homeostasis, neurocardiac interactions, and hypertrophy ( Li et al, 2023 ; Chen et al, 2023 ; Langa et al, 2023 ; Zhou et al, 2023 ). Theoretical reconstructions remain useful in predicting physiological end effects ( Alrabghi et al, 2023 ; Hancox et al, 2023 ).…”

Section: A Hierarchy Of Mechanisms For Ion Channel Modificationmentioning

confidence: 99%

Cardiac arrhythmogenesis: roles of ion channels and their functional modification

Lei,

Salvage,

Jackson

et al. 2024

Front. Physiol.

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Cardiac arrhythmias cause significant morbidity and mortality and pose a major public health problem. They arise from disruptions in the normally orderly propagation of cardiac electrophysiological activation and recovery through successive cardiomyocytes in the heart. They reflect abnormalities in automaticity, initiation, conduction, or recovery in cardiomyocyte excitation. The latter properties are dependent on surface membrane electrophysiological mechanisms underlying the cardiac action potential. Their disruption results from spatial or temporal instabilities and heterogeneities in the generation and propagation of cellular excitation. These arise from abnormal function in their underlying surface membrane, ion channels, and transporters, as well as the interactions between them. The latter, in turn, form common regulatory targets for the hierarchical network of diverse signaling mechanisms reviewed here. In addition to direct molecular-level pharmacological or physiological actions on these surface membrane biomolecules, accessory, adhesion, signal transduction, and cytoskeletal anchoring proteins modify both their properties and localization. At the cellular level of excitation–contraction coupling processes, Ca2+ homeostatic and phosphorylation processes affect channel activity and membrane excitability directly or through intermediate signaling. Systems-level autonomic cellular signaling exerts both acute channel and longer-term actions on channel expression. Further upstream intermediaries from metabolic changes modulate the channels both themselves and through modifying Ca2+ homeostasis. Finally, longer-term organ-level inflammatory and structural changes, such as fibrotic and hypertrophic remodeling, similarly can influence all these physiological processes with potential pro-arrhythmic consequences. These normal physiological processes may target either individual or groups of ionic channel species and alter with particular pathological conditions. They are also potentially alterable by direct pharmacological action, or effects on longer-term targets modifying protein or cofactor structure, expression, or localization. Their participating specific biomolecules, often clarified in experimental genetically modified models, thus constitute potential therapeutic targets. The insights clarified by the physiological and pharmacological framework outlined here provide a basis for a recent modernized drug classification. Together, they offer a translational framework for current drug understanding. This would facilitate future mechanistically directed therapeutic advances, for which a number of examples are considered here. The latter are potentially useful for treating cardiac, in particular arrhythmic, disease.

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Section: A Hierarchy Of Mechanisms For Ion Channel Modificationmentioning

confidence: 99%

Cardiac arrhythmogenesis: roles of ion channels and their functional modification

Lei,

Salvage,

Jackson

et al. 2024

Front. Physiol.

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“…Li et al . [ 39 ] report one such optimized system replicating many anatomical and pathophysiological features of both the individual and combined cardiomyocyte and innervating components mimicking physiological responses in other mammalian systems.…”

Section: Autonomic G-protein-mediated Modulationmentioning

confidence: 99%

Cardiomyocyte electrophysiology and its modulation: current views and future prospects

Huang

Lei

2023

Phil. Trans. R. Soc. B

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Normal and abnormal cardiac rhythms are of key physiological and clinical interest. This introductory article begins from Sylvio Weidmann's key historic 1950s microelectrode measurements of cardiac electrophysiological activity and Singh & Vaughan Williams's classification of cardiotropic targets. It then proceeds to introduce the insights into cardiomyocyte function and its regulation that subsequently emerged and their therapeutic implications. We recapitulate the resulting view that surface membrane electrophysiological events underlying cardiac excitation and its initiation, conduction and recovery constitute the final common path for the cellular mechanisms that impinge upon this normal or abnormal cardiac electrophysiological activity. We then consider progress in the more recently characterized successive regulatory hierarchies involving Ca 2+ homeostasis, excitation–contraction coupling and autonomic G-protein signalling and their often reciprocal interactions with the surface membrane events, and their circadian rhythms. Then follow accounts of longer-term upstream modulation processes involving altered channel expression, cardiomyocyte energetics and hypertrophic and fibrotic cardiac remodelling. Consideration of these developments introduces each of the articles in this Phil. Trans. B theme issue. The findings contained in these articles translate naturally into recent classifications of cardiac electrophysiological targets and drug actions, thereby encouraging future iterations of experimental cardiac electrophysiological discovery, and testing directed towards clinical management. This article is part of the theme issue ‘The heartbeat: its molecular basis and physiological mechanisms’.

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“…A good example of this is a recent work by Li et al, in which they combine CMs and sympathetic neurons, both obtained from hiPSCs, to investigate cardiac hypertrophy. However, it is important to note that in this work the pathological state does not have a genetic origin, but is rather induced by pressor agents [419]. Another limitation of hiPSCbased cardiac disease models is related to the insufficient maturity of the resulting CMs, which hamper the transposability of the results obtained.…”

Section: Generation Of a Hipsc Line From A Ttr Amyloid Cardiomyopathy...mentioning

confidence: 99%

Modelling, design, fabrication and characterization of engineered human myocardium made with melt electrowriting and cardiac cells derived from hiPSCs

Flandes

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The adult human heart has evolved to become a highly specialized organ, whose continuous pumping of blood is critical for survival. However, its ability to regenerate or self-repair following injury is very limited, so consequently any event or disease resulting in damage to the heart poses a serious threat to the patient. Moreover, cardiovascular diseases represent one of the most pressing healthcare concerns nowadays, as they are the leading cause of death worldwide, and the number of cases is only expected to increase in the following years. Despite great progress made over the years to treat cardiovascular diseases, to date there is no therapy able to fully cure a heart that has been damaged. In consequence, there is a dire need to generate new strategies to repair the heart damage and restore the lost cardiac function, as well as to develop accurate modelling platforms to advance in the understanding of disease progression and assess the effectiveness of new drugs. Since its advent, cardiac tissue engineering and regenerative medicine has been regarded as a promising candidate to realise this enormous challenge. Given its interdisciplinary nature, scientific breakthroughs in different areas such as cellular reprogramming, polymer chemistry, and additive manufacturing technologies have resulted in the advancement of cardiac tissue engineering and regenerative medicine over the years. One of such cornerstone discoveries was the generation of induced pluripotent stem cells and subsequent differentiation to different cardiac phenotypes, and the present Thesis revolves around their application to generate patient-specific cardiac disease models and humanised engineered functional cardiac minitissues. Firstly, we reprogrammed peripheral blood mononuclear cells from a transthyretin amyloid cardiomyopathy patient, resulting in the generation of a new cell line carrying a c.128G>A (p.Ser43Asn) mutation in the transthyretin gene. Experiments demonstrated the efficacy and safety of the approach, confirming the pluripotency of the cells, the presence of the disease-causing mutation, and the removal of reprogramming vectors. This cell line, which is now available in a repository, can be used to investigate disease biology, molecular mechanisms and progression; as well as an advanced cellular model to test novel therapeutic strategies. Secondly, we aimed to generate functional human minitissues by combining human cardiomyocytes derived from induced pluripotent stem cells and tridimensional fibrillar scaffolds generated with the technology of melt electrowriting. Compared to conventional two-dimensional cell culture, the cardiac minitissues demonstrated enhanced maturation, with a significant increase in conduction velocity, presence of connexin 43 and expression of cardiac-associated genes such as MYL2, GJA5 and SCN5A, and isoform ratios MYH7/MYH6 and MYL2/MYL7 after 28 days in culture. When investigating the effect of the scaffold fibres on the cells, we found that cardiomyocytes placed close to the fibre were arranged parallel to it, but that alignment was progressively lost towards the centre of the scaffold pore. We then used these data to develop simulations capable of accurately reproducing the experimental performance. In-depth gauging of the structural disposition and intercellular connectivity allowed us to develop an improved computational model able to predict the relationship between cardiac cell alignment and functional performance. This study lays down the path for advancing in the development of in silico tools to predict cardiac biofabricated tissue evolution after generation, and maps the route towards more accurate and biomimetic tissue manufacture. We next aimed at increasing the biological representativity of the cardiac minitissues, by implementing a few changes in cellular (addition of induced pluripotent stem cell-derived cardiac fibroblasts) and hydrogel (substitution of Matrigel for fibrin) composition. We also sought to control cardiomyocyte behaviour based on melt electrowritten scaffold geometry. For this, we hypothesized that diamond-based scaffolds would induce cardiomyocyte contraction in the direction of least mechanical resistance, i.e., the small diagonal of the diamonds. The characterization of the new cardiac minitissues demonstrated functional maturation consistent with the previous work in terms of gene expression and conduction velocity, although the observed low initial cell retention within the scaffold highlighted the need of new strategies to improve cell seeding efficiency. When comparing contractile dynamics between melt electrowritten scaffolds made with square, rectangular, and diamond-shaped pores, we found that the latter resulted in significantly faster, stronger and aligned contraction in the direction that we had anticipated. The potential use of the cardiac minitissues as therapy agents was tested by implanting the constructs in a murine model of chronic myocardial infarction. Compared to controls, implanted animals showed significant improvement, including higher left ventricular ejection fraction and greater wall thickness. Finally, in another attempt to enhance the biological representativity of the constructs, a proof of concept was made to generate melt electrowritten ellipsoidal scaffolds with controlled pore architecture. In summary, the present Thesis revolves around human induced pluripotent stem cells and melt electrowriting as cornerstone tools for cardiac tissue engineering and regenerative medicine efforts. By combining both and iteratively optimising the design and experimental conditions, we were able to generate human functional cardiac minitissues of increased biological relevance.

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Human induced pluripotent stem cell-derived cardiac myocytes and sympathetic neurons in disease modelling

Cited by 8 publications

References 50 publications

Cardiac arrhythmogenesis: roles of ion channels and their functional modification

Cardiac arrhythmogenesis: roles of ion channels and their functional modification

Cardiomyocyte electrophysiology and its modulation: current views and future prospects

Modelling, design, fabrication and characterization of engineered human myocardium made with melt electrowriting and cardiac cells derived from hiPSCs

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