Engineered Macroscale Cardiac Constructs Elicit Human Myocardial Tissue-like Functionality

Valls-Margarit, Maria; Iglesias-García, Olalla; Guglielmo, Claudia Di; Sarlabous, Leonardo; Tadevosyan, Karine; Paoli, Roberto; Comelles, Jordi; Blanco-Almazan, Dolores; Jiménez‐Delgado, Senda; Castillo-Fernandez, Oscar; Samitier, J.; Jané, R.; Martínez, Elena

doi:10.1016/j.stemcr.2019.05.024

Cited by 48 publications

(27 citation statements)

References 49 publications

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“…We have investigated spontaneous APs in 2D-cultured hiPSC-CMs, and in cardiac spheroids with and without CF. It has been hypothesized that 3D culture induces a more mature electric phenotype, although in those studies additional interventions were performed such as contractility training or different media formulations (Ronaldson-Bouchard et al, 2018;LaBarge et al, 2019;Valls-Margarit et al, 2019). Resting membrane potential in immature cardiomyocytes has been reported around −60 and −90 mV in adult cells (Barbuti et al, 2016;Zhao et al, 2018), which is in agreement with our results in monolayer-cultured hiPSC-CMs.…”

Section: Electrical and Contractile Functionsupporting

confidence: 90%

3D Co-culture of hiPSC-Derived Cardiomyocytes With Cardiac Fibroblasts Improves Tissue-Like Features of Cardiac Spheroids

Beauchamp

Jackson

Ozhathil

et al. 2020

Front. Mol. Biosci.

146

106

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Both cardiomyocytes and cardiac fibroblasts (CF) play essential roles in cardiac development, function, and remodeling. Properties of 3D co-cultures are incompletely understood. Hence, 3D co-culture of cardiomyocytes and CF was characterized, and selected features compared with single-type and 2D culture conditions. Methods: Human cardiomyocytes derived from induced-pluripotent stem cells (hiPSC-CMs) were obtained from Cellular Dynamics or Ncardia, and primary human cardiac fibroblasts from ScienCell. Cardiac spheroids were investigated using cryosections and whole-mount confocal microscopy, video motion analysis, scanning-, and transmission-electron microscopy (SEM, TEM), action potential recording, and quantitative PCR (qPCR). Conclusion: We demonstrate that the use of 3D co-culture of hiPSC-CMs and CF is superior over 2D culture conditions for co-culture models and more closely mimicking the native state of the myocardium with relevance to drug development as well as for personalized medicine.

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Section: Electrical and Contractile Functionsupporting

confidence: 90%

3D Co-culture of hiPSC-Derived Cardiomyocytes With Cardiac Fibroblasts Improves Tissue-Like Features of Cardiac Spheroids

Beauchamp

Jackson

Ozhathil

et al. 2020

Front. Mol. Biosci.

146

106

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“…Previous studies have shown the formation of a functional syncytium in 2D cultures mainly due to hypertrophic growth of hiPSC-CMs (Kumar et al, 2019). On the contrary, functional coupling between cardiomyocytes cultured on 3D constructs has been reported only after mechanical or electrical stimulation (Valls-Margarit et al, 2019). Interestingly, in our study, we observed the formation of a functional syncytium of hiPSC-CMs cultured on the coaxial patches, evidenced by the expression of the gap junction protein, Cx-43, and synchronous calcium transients across the patch.…”

Section: Discussionmentioning

confidence: 98%

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.

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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

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“…Although 3D cultures of hiPSC-CMs have great potential to make more matured cardiomyocytes, it is insufficient to do so by itself, and a combination of the above-mentioned maturationpromoting methods worked in 2D must be utilized within a 3D setting, which includes cell-cell interaction (e.g., fibroblasts) (Zhang et al, 2017;King et al, 2019;Valls-Margarit et al, 2019;Yan et al, 2019), hormones (Balistreri et al, 2017;Huang et al, 2020), and electrical and physiological stimulation. Below, we will provide a brief review of the electrical and physiological stimulation applied to 3D cultures to reach the ultimate goal.…”

Section: Enhancing Hipsc-cms Maturation In 3d Culture Systemsmentioning

confidence: 99%

A Brief Review of Current Maturation Methods for Human Induced Pluripotent Stem Cells-Derived Cardiomyocytes

Ahmed¹,

Anzai²,

Chanthra³

et al. 2020

Front. Cell Dev. Biol.

172

154

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Cardiovascular diseases are the leading cause of death worldwide. Therefore, the discovery of induced pluripotent stem cells (iPSCs) and the subsequent generation of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) was a pivotal point in regenerative medicine and cardiovascular research. They constituted an appealing tool for replacing dead and dysfunctional cardiac tissue, screening cardiac drugs and toxins, and studying inherited cardiac diseases. The problem is that these cells remain largely immature, and in order to utilize them, they must reach a functional degree of maturity. To attempt to mimic in vivo environment, various methods including prolonging culture time, co-culture and modulations of chemical, electrical, mechanical culture conditions have been tried. In addition to that, changing the topology of the culture made huge progress with the introduction of the 3D culture that closely resembles the in vivo cardiac topology and overcomes many of the limitations of the conventionally used 2D models. Nonetheless, 3D culture alone is not enough, and using a combination of these methods is being explored. In this review, we summarize the main differences between immature, fetal-like hiPSC-CMs and adult cardiomyocytes, then glance at the current approaches used to promote hiPSC-CMs maturation. In the second part, we focus on the evolving 3D culture model-it's structure, the effect on hiPSC-CMs maturation, incorporation with different maturation methods, limitations and future prospects.

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Engineered Macroscale Cardiac Constructs Elicit Human Myocardial Tissue-like Functionality

Cited by 48 publications

References 49 publications

3D Co-culture of hiPSC-Derived Cardiomyocytes With Cardiac Fibroblasts Improves Tissue-Like Features of Cardiac Spheroids

3D Co-culture of hiPSC-Derived Cardiomyocytes With Cardiac Fibroblasts Improves Tissue-Like Features of Cardiac Spheroids

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

A Brief Review of Current Maturation Methods for Human Induced Pluripotent Stem Cells-Derived Cardiomyocytes

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