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Human mesenchymal stem cells as a gene delivery system to create cardiac pacemakers


Authors >Potapova I, >Plotnikov A, >Lu Z, >Danilo P Jr, >Valiunas V, >Qu J, >Doronin S, >Zuckerman J, >Shlapakova IN, >Gao J, >Pan Z, >Herron AJ, >Robinson RB, >Brink PR, >Rosen MR, >Cohen IS
In >Circ Res (2004) 94(7): 952-959
Cells used in publication Mesench. stem (MSC), human
   Human mesenchymal stem cells (MSC)
   Stem Cells
   Primary Cells
   Species: human
   Tissue Origin: bone marrow
Substrate Plasmid (general)
Topics >Cell morphology/cytoskeleton
>Gene therapy
>Intercellular interaction/communication
>Microscopy of nucleofected cells
Research Area >Cardiovascular
Reporter Gene eGFP
Vector Backbone >pIRES2-EGFP

Research Field

Human mesenchymal stem cells (hMSC) were nucleofected with the cardiac pacemaker gene mHCN2. Physiological properties like the beating rate and the responsiveness to cardiac drugs were tested in vitro and in vivo. A functional ex vivo gene therapy system for the transfer of pacemaker genes was established.

Nucleofection Experiments

For the following experiments, human mesenchymal stem cells (hMSC) nucleofected with mHCN2, were used:

Patch clamp experiments revealed a large time-dependent inward current activation on hyperpolarizations.

After extracellular application of Cs+, the reversal potential could be determined.

A potential advantage of biological over electronic pacemakers is their hormonal regulation. Isoproterenol stimulation increased the current while acetylcholine had no direct effect on the time-dependent current.

Neonatal rat ventricular myocytes cocultured with mHCN2 nucleofected hMSCs showed a reduced maximum diastolic potential consistent with the observed altered threshold potential.

Injection of mHCN2 expressing hMSCs into canine heart led to altered idioventricular rates and the animals developed heart rhythms originating from and pace-mapped to the left ventricle at a site whose origin approximated that of the hMSC injection.

Gap junctions between hMSCs and cardiac myocytes were detected by patch-clamp and microscopy analysis.

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