Biomedical Engineering Reference
In-Depth Information
Embryonic stem cells (ESCs) are pluripotent, allowing them to differentiate into
virtually any cell type. Therefore, genetic engineering of these cells to create a
biological pacemaker is not always necessary, as differentiation can be directed by
changing culturing conditions [20]. However, genetic modification of hESCs provides
a great opportunity in the selection of an appropriate subpopulation. Using the
Į-myosin heavy chain (Į-MHC) promoter driving the expression of the enhanced
green fluorescent protein (EGFP), pacemaker-like cardiomyocytes could be selected
based on fluorescence intensities. In these experiments, a quantitative relation
between EGFP expression and atrial-and pacemaker-like phenotypes of the hEBSc
was shown. Ventricular-like cells proved to be exclusively EGFP negative [23]. In
addition to this application, the combination of the Į-MHC promoter, the EGFP
cassette and a second transgene (e.g., a HCN gene) provides possibilities for both
tracing the optimal subpopulation and further fine-tuning of the hESC properties.
Nevertheless, much has been written about the socio-political fear about the use of
these cell and more technical concerns regarding the expected requirement for
additional immunosuppressive treatment [38, 43].
4 Outlines for a Biological Pacemaker
If a biological pacemaker is to compete with current therapy, various requirements
and safety issues have to be fulfilled. First, there is a need for autonomic regulation.
This may be accomplished by cardiac gene therapy. If one of the HCN channels is
selected, autonomic modulation will occur by adrenergic or muscarinic receptor
pathways that are available in every cardiac myocyte. Changes in intracellular cAMP
caused by these pathways will then alter channel activity.
Second, the site of implantation is important. In electronic pacemakers,
implantation sites are restricted to areas where stable lead positions can be obtained.
With the gene and cell-therapy approaches, it is anticipated that there is much more
freedom to choose a suitable position. This is an advantage if there is cardiac
comorbidity, and arrhythmogenic substrates are present. In these patients, the best
avenue with minimal arrhythmic potential could be selected via catheter-based
intra-cardiac mapping.
Two other issues are important: duration of effect and bio-safety. The functional
duration of pacemaking should be comparable to current (and future) life spans of the
batteries that are used in electronic pacemakers. In a gene therapy approach, this
requires stable and long-term expression of the transgene. When stem cells are used,
the survival, migration and dedifferentiation of these cells are of additional
importance. Gene therapy could provide solutions addressing these problems. For
example, in ischemic hearts, hMSCs survival has improved by transfecting these cells
with a hypoxia-regulated heme oxygenase-1 (HO-1) plasmid. Heme oxygenase-1 is a
key component inhibiting inflammatory cytokines and proapoptotic factors which are
commonly liberated during hypoxia and reoxygenation [47].
With regards to bio-safety, a minimal risk for infections and neoplasias should be
guaranteed. The selection of an appropriate vector system is importantly determined
by these safety requirements. In summary, the ideal system combines stable long-term
expression with low immunogenicity and zero carcinogenicity.
