Abstract
The sodium triple-quantum (TQ) magnetic resonance (MR) signal created by interactions of sodium ions with macromolecules has been demonstrated to be a valuable biomarker for cell viability. The aim of this study was to monitor a cellular response using the sodium TQ signal during inhibition of Na/K-ATPase in living cancer cells (HepG2). The cells were dynamically investigated after exposure to 1 mM ouabain or K+-free medium for 60 min using an MR-compatible bioreactor system. An improved TQ time proportional phase incrementation (TQTPPI) pulse sequence with almost four times TQ signal-to-noise ratio (SNR) gain allowed for conducting experiments with 12–14 × 106 cells using a 9.4 T MR scanner. During cell intervention experiments, the sodium TQ signal increased to 138.9 ± 4.1% and 183.4 ± 8.9% for 1 mM ouabain (n = 3) and K+-free medium (n = 3), respectively. During reperfusion with normal medium, the sodium TQ signal further increased to 169.2 ± 5.3% for the ouabain experiment, while it recovered to 128.5 ± 6.8% for the K+-free experiment. These sodium TQ signal increases agree with an influx of sodium ions during Na/K-ATPase inhibition and hence a reduced cell viability. The improved TQ signal detection combined with this MR-compatible bioreactor system provides a capability to investigate the cellular response of a variety of cells using the sodium TQ MR signal.
Highlights
The intracellular sodium concentration in cells is tightly regulated by the Na/K-ATPase.This ATP-driven pump consumes up to two-thirds of the available cellular energy to maintain a sodium concentration gradient between the intra- and extracellular space [1,2]
For the fixed TQ time proportional phase incrementation (TQTPPI) pulse sequence, we report the transverse relaxation times and the 95%
The fixed TQTPPI pulse sequence with the fixed evolution time yielded an expected theoretical TQ signal-to-noise ratio (SNR) gain in the range of 2.4 to 3.2 for the agarose samples compared to the standard TQTPPI pulse sequence with the evolution time increment
Summary
The intracellular sodium concentration in cells is tightly regulated by the Na/K-ATPase. This ATP-driven pump consumes up to two-thirds of the available cellular energy to maintain a sodium concentration gradient between the intra- and extracellular space [1,2]. Coupled transporters use this stored energy in the electrochemical gradient to transport solutes across the cell membrane. The sodium concentration gradient is the underlying basis for the excitability of muscle cells and for the electric signaling between neurons [3]. The cell viability is linked to the sodium concentration gradient and alterations thereof reflect the early onset of pathophysiological changes
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