Letter to the editor regarding “The influence of melatonin on the heart rhythm – An in vitro simulation with murine embryonic stem cell derived cardiomyocytes”

Understanding how embryonic stem cells and their derivatives interact with the adult host immune system is critical to developing their therapeutic potential. Murine embryonic stem cell-derived hematopoietic progenitors (ESHPs) were generated via coculture with the bone marrow stromal cell line, OP9, and then transplanted into NOD.SCID.Common Gamma Chain (NSG) knockout mice, which lack B, T, and natural killer cells. Compared to control mice transplanted with adult lineage-negative bone marrow (Lin−BM) progenitors, ESHP-transplanted mice attained a low but significant level of donor hematopoietic chimerism. Based on our previous studies, we hypothesized that macrophages might contribute to the low engraftment of ESHPsin vivo. Enlarged spleens were observed in ESHP-transplanted mice and found to contain higher numbers of host F4/80+macrophages compared to BM-transplanted controls.In vivodepletion of host macrophages using clodronate-loaded liposomes improved the ESHP-derived hematopoietic chimerism in the spleen but not in the BM. F4/80+macrophages demonstrated a striking propensity to phagocytose ESHP targetsin vitro. Taken together, these results suggest that macrophages are a barrier to both syngeneic and allogeneic ESHP engraftmentin vivo.

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Beat Rate Variability in Murine Embryonic Stem Cell-Derived Cardiomyocytes: Effect of Antiarrhythmic Drugs

Cellular Physiology and Biochemistry ◽

10.1159/000438657 ◽

2016 ◽

Vol 38 (2) ◽

pp. 646-658 ◽

Cited By ~ 4

Author(s):

Julius Niehoff ◽

Matthias Matzkies ◽

Filomain Nguemo ◽

Jürgen Hescheler ◽

Michael Reppel

Keyword(s):

Stem Cell ◽

Embryonic Stem Cell ◽

Antiarrhythmic Drugs ◽

In Vitro Model ◽

Embryonic Stem ◽

Pharmacological Intervention ◽

Murine Embryonic Stem Cell ◽

Beat Rate ◽

Vitro Model

Background/Aims: Heart rate variability (HRV) refers to the fluctuation of the time interval between consecutive heartbeats in humans. It has recently been discovered that cardiomyocytes derived from human embryonic and induced pluripotent stem cells show beat rate variability (BRV) that is similar to the HRV in humans. In the present study, clinical aspects of HRV were transferred to an in vitro model. The aims of the study were to explore the BRV in murine embryonic stem cell (mESC)-derived cardiomyocytes and to demonstrate the influence of antiarrhythmic drugs on BRV as has been shown in clinical trials previously. Methods: The Microelectrode Array (MEA) technique was used to perform short-term recordings of extracellular field potentials (FPs) of spontaneously beating cardiomyocytes derived from mESCs (D3 cell line, αPig-44). Offline analysis was focused on time domain and nonlinear methods. Results: The Poincaré-Plot analysis of measurements without pharmacological intervention revealed that three different shapes of scatter plots occurred most frequently. Comparable shapes have been described in clinical studies before. The antiarrhythmic drugs Ivabradine, Verapamil and Sotalol augmented BRV, whereas Flecainide decreased BRV parameters at low concentrations (SDSD 79.0 ± 8.7% of control at 10-9 M, p < 0.05) and increased variability measures at higher concentrations (SDNN 258.8 ± 42.7% of control at 10-5 M, p < 0.05). Amiodarone and Metoprolol did not alter BRV significantly. Conclusions: Spontaneously beating cardiomyocytes derived from mESCs showed BRV that appears to be similar to the HRV known from humans. Antiarrhythmic drugs affected BRV parameters similar to clinical observations. Therefore, our study demonstrates that this in vitro model can contribute to a better understanding of electrophysiological properties of mESC-derived cardiomyocytes and might serve as a valuable tool for drug safety screening.

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