Stem cell–based biological pacemakers from proof of principle to therapy: a review

Abstract

Electronic pacemakers are the standard therapy for bradycardia related symptoms but have shortcomings. Over the past 15 years experimental evidence has demonstrated that gene and cell-based therapies can create a biological pacemaker. Recently, physiologically acceptable rates have been reported with an adenovirus-based approach. But adenovirus-based protein expression does not last more than 4 weeks, which limits its clinical applicability. Cell-based platforms are potential candidates for longer expression. Currently there are two cell based approaches being tested: 1) Mesenchymal stem cells used as a suitcase for delivering pacemaker genes and 2) Pluripotent stem cells differentiated down a cardiac lineage with endogenous pacemaker activity. This review examines the current achievements in engineering a biological pacemaker, defines the patient population for whom this device would be useful and identifies the challenges still ahead before cell therapy can replace current electronic devices.

A Brief History of Pacemaking

“…Several attempts have shown that in situ delivery of funny channels to defective cardiac muscle by gene-or cell-based methods can be employed in the attempt to develop biological pacemakers, with the aim to replace electronic devices. Exhaustive review work covers this important subject (Robinson et al, 2006;Rosen et al, 2011;Chauveau et al, 2014).…”

Fibrous scaffolds for building hearts and heart parts

“…The SA node is the pacemaker of the heart, responsible for initiation of the heartbeat and the branching Purkinje fibers ensure that impulses are rapidly conducted throughout the heart to synchronize contraction and optimize ejection fraction. Life-threatening arrhythmias resulting from dysfunctional pacing have been revolutionized by electronic pacemakers but their reliance on batteries and electronic control systems highlight potential advantages of biological or bio-electronic tandem approaches to cardiac pacing [76, 77], including genetic engineering [78] and cell implantation [79]. The recent advent of cardiac optogenetics, where transgenic expression of light-gated ion channels permits optical control of cardiac pacing [80, 81] and termination of reentrant electrical activation [82] (e.g., spiral waves), suggests that gene and cell delivery methods can be used to impart light sensitivity on cardiac tissues for - low-energy pacing of target cells [83].…”

Scientific evidence contradicts findings and assumptions of Canadian Safety Panel 6: microwaves act through voltage-gated calcium channel activation to induce biological impacts at non-thermal levels, supporting a paradigm shift for microwave/lower frequency electromagnetic field action

“…When the apparent mechanisms summarized in Table 1 are put together with the calcium channel blocker studies and other studies on widespread changes in calcium fluxes and calcium signaling following microwave EMF exposures, we are left without any alternative, non-VGCC target of EMF action that currently can be studied for its role in producing biological effects in humans. (35) and can be derived from stem cells (79). Two approaches suggest themselves for measuring responses of such cells to EMF exposure: Cells in culture could be monitored for NO production using an NO electrode in the gas phase over the culture, both before and following EMF exposure.…”