Effect of Substrate Mechanics on Cardiomyocyte Maturation and Growth

Tallawi, Marwa; Rai, Ranjana; Boccaccını, Aldo R.; Aifantis, Katerina E.

doi:10.1089/ten.teb.2014.0383

Cited by 67 publications

(82 citation statements)

References 47 publications

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“…An ideal cardiac model should accurately recapitulate the physiology of natural heart, which is a difficult task due to the complex structure and function of the human heart. In past studies, intensive efforts have been made to develop various kinds of scaffolds that mimic the architecture and biophysics of native heart, for example, modulating the electrical conductivity, mechanical stimulation,[4a,23] and anisotropic properties of the scaffolds. These scaffolds could partially enhance the cardiac cell attachment/alignment; facilitate electrical signal propagation and cell maturation.…”

Section: Discussionmentioning

confidence: 99%

High Modulus Conductive Hydrogels Enhance In Vitro Maturation and Contractile Function of Primary Cardiomyocytes for Uses in Drug Screening

Gao

Liu

et al. 2018

Adv Healthcare Materials

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Effective and quick screening and cardiotoxicity assessment are very crucial for drug development. Here, a novel composite hydrogel composed of carbon fibers (CFs) with high conductivity and modulus with polyvinyl alcohol (PVA) is reported. The conductivity of the composite hydrogel PVA/CFs is similar to that of natural heart tissue, and the elastic modulus is close to that of natural heart tissue during systole, due to the incorporation of CFs. PVA/CFs remarkably enhance the maturation of neonatal rat cardiomyocytes (NRCM) in vitro by upregulating the expression of α‐actinin, troponin T, and connexin‐43, activating the signaling pathway of α5 and β1 integrin‐dependent ILK/p‐AKT, and increasing the level of RhoA and hypoxia‐inducible factor‐1α. As a result, the engineered cell sheet–like constructs NRCM@PVA/CFs display much more synchronous, stable, and robust beating behavior than NRCM@PVA. When exposed to doxorubicin or isoprenaline, NRCM@PVA/CFs can retain effective beating for much longer time or change the contractile rate much faster than NRCM@PVA, respectively, therefore representing a promising heart‐like platform for in vitro drug screening and cardiotoxicity assessment.

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Section: Discussionmentioning

confidence: 99%

High Modulus Conductive Hydrogels Enhance In Vitro Maturation and Contractile Function of Primary Cardiomyocytes for Uses in Drug Screening

Gao

Liu

et al. 2018

Adv Healthcare Materials

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“…Subsequent studies have found similar relationships between substrate stress, cardiomyocyte calcium levels, and force generation, as reviewed in [5]. Using cardiomyocytes from quail chick embryos, one study found that the spontaneous beating frequency, as well as the percentage of beating cells, increased as the stiffness of the underlying substrate decreased ([6]).…”

Section: Introductionmentioning

confidence: 91%

The Effect of Substrate Stiffness on Cardiomyocyte Action Potentials

Boothe

Myers

Pok

et al. 2016

Cell Biochem Biophys

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The stiffness of myocardial tissue changes significantly at birth and during neonatal development, concurrent with significant changes in contractile and electrical maturation of cardiomyocytes. Previous studies by our group have shown that cardiomyocytes generate maximum contractile force when cultured on a substrate with a stiffness approximating native cardiac tissue. However, effects of substrate stiffness on the electrophysiology and ion currents in cardiomyocytes have not been fully characterized. In this study, neonatal rat ventricular myocytes were cultured on the surface of flat polyacrylamide hydrogels with elastic moduli ranging from 1 to 25 kPa. Using whole-cell patch clamping, action potentials and L-type calcium currents were recorded. Cardiomyocytes cultured on hydrogels with a 9 kPa elastic modulus, similar to that of native myocardium, had the longest action potential duration. Additionally, the voltage at maximum calcium flux significantly decreased in cardiomyocytes on hydrogels with an elastic modulus higher than 9 kPa, and the mean inactivation voltage decreased with increasing stiffness. Interestingly, the expression of the L-type calcium channel subunit α gene and channel localization did not change with stiffness. Substrate stiffness significantly affects action potential length and calcium flux in cultured neonatal rat cardiomyocytes in a manner that may be unrelated to calcium channel expression. These results may explain functional differences in cardiomyocytes resulting from changes in the elastic modulus of the extracellular matrix, as observed during embryonic development, in ischemic regions of the heart after myocardial infarction, and during dilated cardiomyopathy.

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“…The above-mentioned methods have also been used to elucidate the role of mechanical signaling in hypertrophic signaling in both a physiological and pathological context [208,209]. In this section, a review of the relevant literature focuses on efforts to enhance CM function and phenotype via mechanical stimulation as well as studies aimed at utilizing mechanical stimulation as a tool to understand hypertrophic signaling in CMs (Note: for a more complete review, see Zimmermann et al in this issue or Tallawi et al [210]).…”

Section: Mechanical Stimulation Of Cardiac Cells and Tissuesmentioning

confidence: 99%

Electrical and mechanical stimulation of cardiac cells and tissue constructs

Stoppel

Kaplan

Black

2016

Advanced Drug Delivery Reviews

224

190

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The field of cardiac tissue engineering has made significant strides over the last few decades, highlighted by the development of human cell derived constructs that have shown increasing functional maturity over time, particularly using bioreactor systems to stimulate the constructs. However, the functionality of these tissues is still unable to match that of native cardiac tissue and many of the stem-cell derived cardiomyocytes display an immature, fetal like phenotype. In this review, we seek to elucidate the biological underpinnings of both mechanical and electrical signaling, as identified via studies related to cardiac development and those related to an evaluation of cardiac disease progression. Next, we review the different types of bioreactors developed to individually deliver electrical and mechanical stimulation to cardiomyocytes in vitro in both two and three-dimensional tissue platforms. Reactors and culture conditions that promote functional cardiomyogenesis in vitro are also highlighted. We then cover the more recent work in the development of bioreactors that combine electrical and mechanical stimulation in order to mimic the complex signaling environment present in vivo. We conclude by offering our impressions on the important next steps for physiologically relevant mechanical and electrical stimulation of cardiac cells and engineered tissue in vitro.

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Effect of Substrate Mechanics on Cardiomyocyte Maturation and Growth

Cited by 67 publications

References 47 publications

High Modulus Conductive Hydrogels Enhance In Vitro Maturation and Contractile Function of Primary Cardiomyocytes for Uses in Drug Screening

High Modulus Conductive Hydrogels Enhance In Vitro Maturation and Contractile Function of Primary Cardiomyocytes for Uses in Drug Screening

The Effect of Substrate Stiffness on Cardiomyocyte Action Potentials

Electrical and mechanical stimulation of cardiac cells and tissue constructs

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