Genetically engineered cardiac pacemaker: Stem cells transfected with HCN2 gene and myocytes—A model

Abstract

Abstract One of the successfully tested methods to design genetically engineered cardiac pacemaker cells consists in transfecting a human mesenchymal stem cell ( hMSC ) with a HCN2 gene and connecting it to a myocyte. We develop and study a mathematical model, describing a myocyte connected to a hMSC transfected with a HCN2 gene. The cardiac action potential is described both with the simple Beeler–Reuter model, as well as with the elaborate dynamic Luo–Rudy model. The HCN2 channel is described by fitting electrophysiological records, in the spirit of Hodgkin–Huxley. The model shows that oscillations can occur in a pair myocyte-stem cell, that was not observed in the experiments yet. The model predicted that: (1) HCN pacemaker channels can induce oscillations only if the number of expressed I K 1 channels is low enough. At too high an expression level of I K 1 channels, oscillations cannot be induced, no matter how many pacemaker channels are expressed. (2) At low expression levels of I K 1 channels, a large domain of values in the parameter space ( n , N ) exists, where oscillations should be observed. We denote N the number of expressed pacemaker channels in the stem cell, and n the number of gap junction channels coupling the stem cell and the myocyte. (3) The expression levels of I K 1 channels observed in ventricular myocytes, both in the Beeler–Reuter and in the dynamic Luo–Rudy models are too high to allow to observe oscillations. With expression levels below ∼ 1 / 4 of the original value, oscillations can be observed. The main consequence of this work is that in order to obtain oscillations in an experiment with a myocyte-stem cell pair, increasing the values of n , N is unlikely to be helpful, unless the expression level of I K 1 has been reduced enough. The model also allows us to explore levels of gene expression not yet achieved in experiments, and could be useful to plan new experiments, aimed at improving the robustness of the oscillations.