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Dominant rule of community effect in synchronized beating behavior of cardiomyocyte networks.

ABSTRACT: Exploiting the combination of latest microfabrication technologies and single cell measurement technologies, we can measure the interactions of single cells, and cell networks from "algebraic" and "geometric" perspectives under the full control of their environments and interactions. However, the experimental constructive single cell-based approach still remains the limitations regarding the quality and condition control of those cells. To overcome these limitations, mathematical modeling is one of the most powerful complementary approaches. In this review, we first explain our on-chip experimental methods for constructive approach, and we introduce the results of the "community effect" of beating cardiomyocyte networks as an example of this approach. On-chip analysis revealed that (1) synchronized interbeat intervals (IBIs) of cell networks were followed to the more stable beating cells even their IBIs were slower than the other cells, which is against the conventional faster firing regulation or "overdrive suppression," and (2) fluctuation of IBIs of cardiomyocyte networks decreased according to the increase of the number of connected cells regardless of their geometry. The mathematical simulation of this synchronous behavior of cardiomyocyte networks also fitted well with the experimental results after incorporating the fluctuation-dissipation theorem into the oscillating stochastic phase model, in which the concept of spatially arranged cardiomyocyte networks was involved. The constructive experiments and mathematical modeling indicated the dominant rule of synchronization behavior of beating cardiomyocyte networks is a kind of stability-oriented synchronization phenomenon as the "community effect" or a fluctuation-dissipation phenomenon. Finally, as a practical application of this approach, the predictive cardiotoxicity is introduced.

SUBMITTER: Yasuda K

PROVIDER: S-EPMC7242600 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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Dominant rule of community effect in synchronized beating behavior of cardiomyocyte networks.

Yasuda Kenji K

Biophysical reviews 20200401 2

Exploiting the combination of latest microfabrication technologies and single cell measurement technologies, we can measure the interactions of single cells, and cell networks from "algebraic" and "geometric" perspectives under the full control of their environments and interactions. However, the experimental constructive single cell-based approach still remains the limitations regarding the quality and condition control of those cells. To overcome these limitations, mathematical modeling is one ...[more]

PMID: 32367300

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Project description:A common denominator for patients with heart failure is the correlation between elevated serum levels of proinflammatory cytokines and adverse clinical outcomes. Furthermore, lipoxygenase-induced inflammation is reportedly involved in the pathology of heart failure. Cardiac fibroblasts, which are abundant in cardiac tissue, are known to be activated by inflammation. We previously showed high expression of the lipoxygenase arachidonate 15 lipoxygenase (ALOX15), which catalyzes the conversion of arachidonic acid to 15-hydroxy eicosatetraenoic acid (15-HETE), in ischemic cardiac tissue. The exact roles of ALOX15 and 15-HETE in the pathogenesis of heart failure are however unknown. Biopsies were collected from all chambers of explanted failing human hearts from heart transplantation patients, as well as from the left ventricles from organ donors not suffering from chronic heart failure. Biopsies from the left ventricles underwent quantitative immunohistochemical analysis for ALOX15/B. Gene expression of ALOX enzymes, as well as 15-HETE levels, were examined in cardiac fibroblasts which had been cultured in either hypoxic or normoxic conditions after isolation from failing hearts. After the addition of fibroblast supernatants to human induced pluripotent stem cell-derived cardiomyocytes, intracellular calcium concentrations were measured to examine the effect of paracrine signaling on cardiomyocyte beating frequency. While ALOX15 and ALOX15B were expressed throughout failing hearts as well as in hearts from organ donors, ALOX15 was expressed at significantly higher levels in donor hearts. Hypoxia resulted in a significant increase in gene and protein expression of ALOX15 and ALOX15B in fibroblasts isolated from the different chambers of failing hearts. Finally, preconditioned medium from hypoxic fibroblasts decreased the beating frequency of human cardiomyocytes derived from induced pluripotent stem cells in an ALOX15-dependent manner. In summary, our results demonstrate that ALOX15/B signaling by hypoxic cardiac fibroblasts may play an important role in ischemic cardiomyopathy, by decreasing cardiomyocyte beating frequency.

Dataset Information

Dominant rule of community effect in synchronized beating behavior of cardiomyocyte networks.

Publications

Dominant rule of community effect in synchronized beating behavior of cardiomyocyte networks.

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