Generating 3D human cardiac constructs from pluripotent stem cells

Liu, Chang; Feng, Xing; Li, Guoping; Gokulnath, Priyanka; Xiao, Junjie

doi:10.1016/j.ebiom.2022.103813

Cited by 29 publications

(59 citation statements)

References 109 publications

(148 reference statements)

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“…Gene expression changes, protein abundance and mitochondrial effects, though beyond the scope of this study are warranted to better understand differences in neuronal subtypes and their downstream signaling mechanisms post CCM stimulation. Some other general limitations of in vitro iPSC models are discussed elsewhere in detail (Feaster et al, 2021 ; Liu et al, 2022 ).…”

Section: Discussionmentioning

confidence: 99%

Human in vitro neurocardiac coculture ( iv NCC ) assay development for evaluating cardiac contractility modulation

Narkar

Feaster

Casciola

et al. 2022

Physiological Reports

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Two of the most prominent organ systems, the nervous and the cardiovascular systems, are intricately connected to maintain homeostasis in mammals. Recent years have shown tremendous efforts toward therapeutic modulation of cardiac contractility and electrophysiology by electrical stimulation. Neuronal innervation and cardiac ganglia regulation are often overlooked when developing in vitro models for cardiac devices, but it is likely that peripheral nervous system plays a role in the clinical effects. We developed an in vitro neurocardiac coculture ( iv NCC) model system to study cardiac and neuronal interplay using human induced pluripotent stem cell (hiPSC) technology. We demonstrated significant expression and colocalization of cardiac markers including troponin, α‐actinin, and neuronal marker peripherin in neurocardiac coculture. To assess functional coupling between the cardiomyocytes and neurons, we evaluated nicotine‐induced β‐adrenergic norepinephrine effect and found beat rate was significantly increased in iv NCC as compared to monoculture alone. The developed platform was used as a nonclinical model for the assessment of cardiac medical devices that deliver nonexcitatory electrical pulses to the heart during the absolute refractory period of the cardiac cycle, that is, cardiac contractility modulation (CCM) therapy. Robust coculture response was observed at 14 V/cm (5 V, 64 mA), monophasic, 2 ms pulse duration for pacing and 20 V/cm (7 V, 90 mA) phase amplitude, biphasic, 5.14 ms pulse duration for CCM. We observed that the CCM effect and kinetics were more pronounced in coculture as compared to cardiac monoculture, supporting a hypothesis that some part of CCM mechanism of action can be attributed to peripheral nervous system stimulation. This study provides novel characterization of CCM effects on hiPSC‐derived neurocardiac cocultures. This innervated human heart model can be further extended to investigate arrhythmic mechanisms, neurocardiac safety, and toxicity post‐chronic exposure to materials, drugs, and medical devices. We present data on acute CCM electrical stimulation effects on a functional and optimized coculture using commercially available hiPSC‐derived cardiomyocytes and neurons. Moreover, this study provides an in vitro human heart model to evaluate neuronal innervation and cardiac ganglia regulation of contractility by applying CCM pulse parameters that closely resemble clinical setting. This iv NCC platform provides a potential tool for investigating aspects of cardiac and neurological device safety and performance.

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Section: Discussionmentioning

confidence: 99%

Human in vitro neurocardiac coculture ( iv NCC ) assay development for evaluating cardiac contractility modulation

Narkar

Feaster

Casciola

et al. 2022

Physiological Reports

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“…150,151 These cells can be transdifferentiated into cardiomyocytes (called hPSC-derived cardiomyocytes, hPSC-CMs) for analysis (Figure 7A). 152,153 It has been found that multicellular cardiac microtissues induced by hiPSCs in vitro could be used to model arrhythmias and other cardiac diseases. 154,155 By simulating the external environment of the cells through microfluidic systems, those low-cost and high-throughput iPSCderived cardiac models have shown great advantages in disease modeling.…”

Section: Ooc Technology For Cardiac Regenerationmentioning

confidence: 99%

Advances in organ‐on‐a‐chip for the treatment of cardiovascular diseases

Liu,

Wang

2023

MedComm – Biomaterials and Applications

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Cardiovascular disease (CVD) is currently a serious and growing public health problem. In tackling this challenge, organ‐on‐chip (OoC) technology, combined with cell culture and microfluidics, presents a powerful approach for constructing sophisticated tissue models in vitro that can simulate the physiological and pathological microenvironments of human organs. Nowadays, OoC technology has emerged as a pivotal tool in advancing our understanding of CVD pathogenesis, facilitating tissue regeneration studies, conducting efficient drug screening, and assessing therapeutic effects. Moreover, it offers a diverse array of study platforms for preclinical research, fostering innovative approaches towards combating CVD and improving patient outcomes. In this review, we first present the key advantages of OoC technology, including its highly relevant physiological microenvironment, incorporation of integrated functions, and the possibility of the construction of multiorgan‐on‐a‐chip through microfluidic linkage. Then, we summarized the role of OoC in the construction of disease pathological models, which provides a new channel for the exploration of disease pathological mechanisms. Moreover, we discuss the application of this technology in cardiac regeneration and drug screening. Finally, we discuss the challenges of tissue models constructed based on OoC technology and the prospects of this innovative approach.

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“…It has been used as a basic principle for spheroid generation, such as hanging drops, low-binding surfaces, and spinner flasks. [21][22][23] Endogenous components of the ECM, such as fibronectin, are, along with integrins, the main recognition molecules for cell adhesion. [24] Fibronectin is usually glycosylated and contains a cell adhesion sequence (arginine-glycine-aspartic acid [RGD]), which can promote cell-substratum detachment and cell-cell adhesion by binding to integrins.…”

Section: Introductionmentioning

confidence: 99%

Supramolecular Assemblies of Glycopeptides Enhance Gap Junction Maturation of Human Induced Pluripotent Stem Cell‐Derived Cardiomyocytes via Inducing Spheroids Formation to Optimize Cardiac Repair

et al. 2023

Adv Healthcare Materials

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Stem cell‐based therapies have demonstrated significant potential for use in heart regeneration. An effective paradigm for heart repair in rodent and large animal models is the transplantation of human induced pluripotent stem cell‐derived cardiomyocytes (hiPSC‐CMs). Despite this, the functional and phenotypical immaturity of 2D‐cultured hiPSC‐CMs, particularly their low electrical integration, poses a caveat for clinical translation. In this study, a supramolecular assembly of a glycopeptide containing a cell adhesion motif‐RGD, and saccharide‐glucose (Bio‐Gluc‐RGD) is designed to enable the 3D spheroid formation of hiPSC‐CMs, promoting cell‐cell and cell‐matrix interactions that occur during spontaneous morphogenesis. HiPSC‐CMs in spheroids are prone to be phenotypically mature and developed robust gap junctions via activation of the integrin/ILK/p‐AKT/Gata4 pathway. Monodispersed hiPSC‐CMs encapsulated in the Bio‐Gluc‐RGD hydrogel are more likely to form aggregates and, therefore, survive in the infarcted myocardium of mice, accompanied by more robust gap junction formation in the transplanted cells, and hiPSC‐CMs delivered with the hydrogels also displayed angiogenic effect and anti‐apoptosis capacity in the peri‐infarct area, enhancing their overall therapeutic efficacy in myocardial infarction. Collectively, the findings illustrate a novel concept for modulating hiPSC‐CM maturation by spheroid induction, which has the potential for post‐MI heart regeneration.

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Generating 3D human cardiac constructs from pluripotent stem cells

Cited by 29 publications

References 109 publications

Human in vitro neurocardiac coculture ( iv NCC ) assay development for evaluating cardiac contractility modulation

Human in vitro neurocardiac coculture ( iv NCC ) assay development for evaluating cardiac contractility modulation

Advances in organ‐on‐a‐chip for the treatment of cardiovascular diseases

Supramolecular Assemblies of Glycopeptides Enhance Gap Junction Maturation of Human Induced Pluripotent Stem Cell‐Derived Cardiomyocytes via Inducing Spheroids Formation to Optimize Cardiac Repair

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