Engineering hiPSC cardiomyocyte in vitro model systems for functional and structural assessment

Schroer, Alison K.; Pardon, Gaspard; Castillo, Erica A; Blair, Cheavar A.; Pruitt, Beth L.

doi:10.1016/j.pbiomolbio.2018.12.001

Cited by 18 publications

(22 citation statements)

References 224 publications

(324 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Cardiovascular diseases (CVDs) are the number one cause of morbidity in North America. However, the development of therapeutics for CVDs has been limited by the paucity of efficient model systems for drug screening and toxicology studies (Schroer et al, 2019). Most pharmacological studies make use of primary cell lines or model organisms like rodents, rabbits, pigs, and non-human primates for assessing the effect of putative drug molecules (Savoji et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

Scalable Biomimetic Coaxial Aligned Nanofiber Cardiac Patch: A Potential Model for “Clinical Trials in a Dish”

Kumar

Sridharan

Palaniappan

et al. 2020

Front. Bioeng. Biotechnol.

View full text Add to dashboard Cite

Recent advances in cardiac tissue engineering have shown that human inducedpluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) cultured in a threedimensional (3D) micro-environment exhibit superior physiological characteristics compared with their two-dimensional (2D) counterparts. These 3D cultured hiPSC-CMs have been used for drug testing as well as cardiac repair applications. However, the fabrication of a cardiac scaffold with optimal biomechanical properties and high biocompatibility remains a challenge. In our study, we fabricated an aligned polycaprolactone (PCL)-Gelatin coaxial nanofiber patch using electrospinning. The structural, chemical, and mechanical properties of the patch were assessed by scanning electron microscopy (SEM), immunocytochemistry (ICC), Fourier-transform infrared spectroscopy (FTIR)-spectroscopy, and tensile testing. hiPSC-CMs were cultured on the aligned coaxial patch for 2 weeks and their viability [lactate dehydrogenase (LDH assay)], morphology (SEM, ICC), and functionality [calcium cycling, multielectrode array (MEA)] were assessed. Furthermore, particle image velocimetry (PIV) and MEA were used to evaluate the cardiotoxicity and physiological functionality of the cells in response to cardiac drugs. Nanofibers patches were comprised of highly aligned core-shell fibers with an average diameter of 578 ± 184 nm. Acellular coaxial patches were significantly stiffer than gelatin alone with an ultimate tensile strength of 0.780 ± 0.098 MPa, but exhibited gelatin-like biocompatibility. Furthermore, hiPSC-CMs cultured on the surface of these aligned coaxial patches (3D cultures) were elongated and rod-shaped with well-organized sarcomeres, as observed by the expression of cardiac troponin-T and α-sarcomeric actinin. Additionally, hiPSC-CMs cultured on these coaxial patches formed a functional syncytium evidenced by the expression of connexin-43 (Cx-43) and

show abstract

Section: Introductionmentioning

confidence: 99%

Scalable Biomimetic Coaxial Aligned Nanofiber Cardiac Patch: A Potential Model for “Clinical Trials in a Dish”

Kumar

Sridharan

Palaniappan

et al. 2020

Front. Bioeng. Biotechnol.

View full text Add to dashboard Cite

show abstract

“…Human PSCs also remain a highly attractive cells source for personalized medicine applications due to the ease with which their genomes can be modified using state-of-the art genome editing technologies (167)(168)(169) allowing (i) the introduction of disease-associated genetic variants in PSCs of a healthy individual and (ii) 'genetic curing' of patient-derived PSCs (154,170,171). Of the various approaches to improve PSCbased arrhythmia models, the engineering of 3D cardiac tissue constructs including heart-on-a-chip devices is of particular interest as this will allow assessment of cardiac electrical activity in a more realistic setting than can be provided by 2D CM monocultures (165,(172)(173)(174). This is nicely illustrated by a recent study of Goldfracht et al, who generated ring-shaped atrial and ventricular EHTs from hESCs showing heart chamber-specific differences in gene expression, electrophysiology, contractile properties and pharmacology (175).…”

Section: (Human) Psc-derived Atrial(-like) Cmsmentioning

confidence: 99%

Multicellular In vitro Models of Cardiac Arrhythmias: Focus on Atrial Fibrillation

Gorp

Trines

Pijnappels

et al. 2020

Front. Cardiovasc. Med.

View full text Add to dashboard Cite

Atrial fibrillation (AF) is the most common cardiac arrhythmia in clinical practice with a large socioeconomic impact due to its associated morbidity, mortality, reduction in quality of life and health care costs. Currently, antiarrhythmic drug therapy is the first line of treatment for most symptomatic AF patients, despite its limited efficacy, the risk of inducing potentially life-threating ventricular tachyarrhythmias as well as other side effects. Alternative, in-hospital treatment modalities consisting of electrical cardioversion and invasive catheter ablation improve patients' symptoms, but often have to be repeated and are still associated with serious complications and only suitable for specific subgroups of AF patients. The development and progression of AF generally results from the interplay of multiple disease pathways and is accompanied by structural and functional (e.g., electrical) tissue remodeling. Rational development of novel treatment modalities for AF, with its many different etiologies, requires a comprehensive insight into the complex pathophysiological mechanisms. Monolayers of atrial cells represent a simplified surrogate of atrial tissue well-suited to investigate atrial arrhythmia mechanisms, since they can easily be used in a standardized, systematic and controllable manner to study the role of specific pathways and processes in the genesis, perpetuation and termination of atrial arrhythmias. In this review, we provide an overview of the currently available two-and three-dimensional multicellular in vitro systems for investigating the initiation, maintenance and termination of atrial arrhythmias and AF. This encompasses cultures of primary (animal-derived) atrial cardiomyocytes (CMs), pluripotent stem cell-derived atrial-like CMs and (conditionally) immortalized atrial CMs. The strengths and weaknesses of each of these model systems for studying atrial arrhythmias will be discussed as well as their implications for future studies.

show abstract

“…In addition to recreating the organization of primary tissue, 3D engineered cellular constructs, termed engineered heart tissues, have the advantage of facilitating the co-culture of different cell types (see Figure 1(c)), which has been demonstrated to enhance the maturity of iPSC-cardiomyocytes. 18,[71][72][73] Cellular organization and composition of the human heart tissue are complex and difficult to fully replicate in vitro. In addition to cardiomyocytes, various cell types exist in the heart in high numbers relative to cardiomyocytes, such as endothelial cells, smooth muscle cells, and different types of stromal fibroblasts organized within an intricate and well-defined three-dimensional network of extracellular matrix proteins.…”

Section: Cardiomyocytesmentioning

confidence: 99%

Microengineered systems with iPSC-derived cardiac and hepatic cells to evaluate drug adverse effects

Dame

Ribeiro

2020

Exp Biol Med (Maywood)

View full text Add to dashboard Cite

Hepatic and cardiac drug adverse effects are among the leading causes of attrition in drug development programs, in part due to predictive failures of current animal or in vitro models. Hepatocytes and cardiomyocytes differentiated from human induced pluripotent stem cells (iPSCs) hold promise for predicting clinical drug effects, given their human-specific properties and their ability to harbor genetically determined characteristics that underlie inter-individual variations in drug response. Currently, the fetal-like properties and heterogeneity of hepatocytes and cardiomyocytes differentiated from iPSCs make them physiologically different from their counterparts isolated from primary tissues and limit their use for predicting clinical drug effects. To address this hurdle, there have been ongoing advances in differentiation and maturation protocols to improve the quality and use of iPSC-differentiated lineages. Among these are in vitro hepatic and cardiac cellular microsystems that can further enhance the physiology of cultured cells, can be used to better predict drug adverse effects, and investigate drug metabolism, pharmacokinetics, and pharmacodynamics to facilitate successful drug development. In this article, we discuss how cellular microsystems can establish microenvironments for these applications and propose how they could be used for potentially controlling the differentiation of hepatocytes or cardiomyocytes. The physiological relevance of cells is enhanced in cellular microsystems by simulating properties of tissue microenvironments, such as structural dimensionality, media flow, microfluidic control of media composition, and co-cultures with interacting cell types. Recent studies demonstrated that these properties also affect iPSC differentiations and we further elaborate on how they could control differentiation efficiency in microengineered devices. In summary, we describe recent advances in the field of cellular microsystems that can control the differentiation and maturation of hepatocytes and cardiomyocytes for drug evaluation. We also propose how future research with iPSCs within engineered microenvironments could enable their differentiation for scalable evaluations of drug effects. Impact statement Cardiac and hepatic adverse drug effects are among the leading causes of attrition in preclinical and clinical drug development programs as well as marketing withdrawals. The insufficiency of animal testing models has led to considerable interest in the employment of cardiac and hepatic models using human-induced pluripotent stem cells (iPSCs) for drug toxicity testing. However, current batches of iPSC-derived cardiomyocytes and hepatocytes are variable and not matured as adult primary tissues, which limit their prediction of drug effects. This article discusses how the use of microfluidics can create microenvironments to better control differentiation protocols and increase the physiological relevance of iPSC-derived cardiomyocytes and hepatocytes. Development and standardization of technologies will enable evaluation of the potential value of cellular microsystems to improve the in vitro models used in drug development programs. Future steps in this field include controlled connections of organ systems to better recreate clinical metabolism and pharmacokinetics.

show abstract

Engineering hiPSC cardiomyocyte in vitro model systems for functional and structural assessment

Cited by 18 publications

References 224 publications

Scalable Biomimetic Coaxial Aligned Nanofiber Cardiac Patch: A Potential Model for “Clinical Trials in a Dish”

Scalable Biomimetic Coaxial Aligned Nanofiber Cardiac Patch: A Potential Model for “Clinical Trials in a Dish”

Multicellular In vitro Models of Cardiac Arrhythmias: Focus on Atrial Fibrillation

Microengineered systems with iPSC-derived cardiac and hepatic cells to evaluate drug adverse effects

Contact Info

Product

Resources

About