MPS with microcirculation mimicking the in vivo transport, which includes continuous exchange of nutrients, constant exposure of the tissue to fresh drug compounds, and removal of metabolic waste products.
iPSC-derived cardiomyocytes plated on a micropatterned 96-half-well plate. Micropatterning aligns cells similarly to structure of heart muscle in-vivo.
In cardiomyocytes, pacemaking arises from an interplay between hyperpolarizing and dominating depolarizing currents during the phase 4 depolarization period (the period between repolarization and the rising phase of the subsequent action potential). In the sinoatrial node, the hyperpolarization-induced inward current (HCN isoforms) of cardiac pacemaker cells plays a major role in pacemaking (47). However, in the case of our G-node where stem cell-derived CMs and NRVMs supposedly lack the expression of HCNs, the pacemaking potentials are a result of inward currents produced by Ca2+ cycling (driven by rhythmic releases of intracellular Ca2+ from the sarco/endoplasmic reticulum).
The remaining question was how a region of cells initiate coordinated pacemaking and how this relates to electrical cell-to-cell coupling. The geometrical node design plays a crucial role here because the current being exchanged between individual cells of different membrane potentials is locally accumulated in the membrane capacitance at the edges and is reflected at the tissue edges. The reflection of intracellular currents at the tissue edges synchronizes the spontaneous activity in the structurally isolated small tissues like a G-node and increases their firing rate. The mechanism of reflection at the corners of cultures behave similarly (since downstream impedance is reduced), in particular the anterior corners with acute angles albeit less than in the G-node, and as a result, firing is enhanced in the whole anterior side.
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