Biomedical Engineering Reference
In-Depth Information
action potentials in the epicardium coincided with the injection site of the
spontaneously beating hEBs, as identified by their GFP fluorescence.
Taken together, this study demonstrates that bio-logical pacemakers derived from
hESCs are capable of pacing recipient ventricular cardiomyocytes in vitro and
myocardium in vivo.
4 Adult Stem Cell-Derived Biological Pacemaker
As an alternative cell source, we used adult cardiac stem cells in order to derive
biological pacemakers. The heart had long been thought to be a terminally
differentiated organ incapable of regeneration. The view held that the cardiomyocytes
that we are born with during embryonic and fetal development do not grow in
numbers but only in size. Only recently, this dogma has been challenged and refuted
to form a new paradigm by the discovery of cardiac stem cells (CSCs) [5, 45-47, 54,
56]. The heart is now regarded as a self-renewing organ in which myocyte
regeneration occurs throughout the organism's lifespan [2].
We have established a straightforward isolation technique that allow us to retrieve
and amplify >10
6
human adult cardiac stem cells in less than 4 weeks from a single
endomyocardial biopsy specimen [68]. The adult cardiac stem cells differentiated into
car-diomyocytes with cardiac specific markers [68, 69]. These adult stem cells self-
aggregate to form three-dimensional structures named cardiospheres and, upon co-
culturing with rat ventricular myocytes, could differentiate into a spontaneously
contracting cardiac tissue with innate pacemaker function [16]. The use of adult stem
cells circumvents complications associated with human embryonic stem cells such as
obvious ethical concerns [60], immunogenic reactions against the donor cells [21],
and a visible degree of teratoma formation [53]. The autologous cell therapy using
adult cardiac stem cells thus presents a unique possibility in developing biological
pacemakers.
5 Creation of a Biological Pacemaker by Cell Fusion
In a previous study, human mesenchymal stem cells (hMSCs) transfected with a
mouse pacemaker ion channel gene, mHCN2, were shown to induce spontaneous
pacing when injected into canine left ventricular wall [57]. A key prerequisite to this
approach is a high degree of gap-junctional coupling between the donor (hMSCs) and
the host tissue. However, such gap junctional coupling may or may not be stable over
time. Indeed, many of the major forms of human heart disease with increased
arrhythmic risk coincide with gap junction remodeling and decreased cell-cell cou-
pling [73]. In addition, frequency tuning of the stem cell-derived biological
pacemaker would require further genetic manipulations. Thus, we explored the
feasibility of converting normally quiescent ventricular myocytes into pacemakers by
somatic cell fusion [14]. The idea is to create chemically induced fusion between
myocytes and syngeneic fibroblasts engineered to express pacemaker ion channels,
HCN1.
