Biomedical Engineering Reference
In-Depth Information
fact that skeletal muscle cells, unlike heart cells, are electrically isolated by the
absence of gap junctions, or protein connections between cell membranes that allow
neighboring cells to communicate with each other through the exchange of ions and
other electrical signals. These arrhythmias could be terminated by nitrendipine, an
L-type calcium channel blocker, but not by the Na channel blocker lidocaine
(Abraham et al.
2005
). In gene therapy experiments, production of connexin 43 was
increased by injecting a viral vector carrying the gene that codes for the gap-junction
protein into the cultured cells. Genetic modification of myoblasts to express the gap
junction protein connexin 43 decreases arrhythmogenicity in hearts transplanted with
myoblasts. Combining gene therapy to replace connexin 43 along with myoblast
transplants may prevent the development of potentially fatal arrhythmias in patients.
ESCs for Correction of Congenital Heart Defects
Researchers at Memorial Sloan-Kettering Cancer Center in New York have shown
that ESCs, injected into embryos of mice genetically predisposed to develop a lethal
cardiac defect, prevented the development of this disorder (Fraidenraich et al.
2004
).
Previous studies had demonstrated a relationship between the presence of a specific
protein called Id during embryonic growth and the normal development of capillar-
ies and blood vessels. Two important molecules are implicated in signaling from the
ESCs to the Id knock-out cells: insulin-like growth factor 1 (IGF-I) and WNT5a.
The former molecule is a long-range acting factor, and the latter is a short-range
factor and a member of the family of WNT proteins. Both molecules are implicated
in heart development and cancer. Mice engineered without Id, “Id knock-out” mice,
display severe cardiac defects and die at mid-gestation. Following injection of ESCs
into these mice, not only did the daughter ESCs incorporate into the defective
embryonic heart but they also released biological factors preventing neighboring
heart cells from developing into defective tissue. The result was that 50% of the
mice fated to die in utero were born with healthy hearts. The authors demonstrated
that IGF-I injected into the mother can cross the placenta and influence fetal cardiac
development in the Id knock-out embryo. The Id knock-out embryos were born, but
with partial rescue of cardiac defects and abnormal gene expression profiles. As a
result, Id knock-out pups whose mothers were manipulated bypassed mid-gestation
lethality, although they died during the first 2 days of life. On the other hand,
WNT5a had the ability to correct the abnormal gene expression profiles of the Id
knock-out hearts to normal levels. These two mechanisms (long- and short-range
action) in conjunction may account for the full correction of the cardiac defects.
Cardiac Progenitors Cells for Treatment of Heart Disease
Because fully developed heart cells do not divide, the organ is viewed as incapable
of regeneration after injury but this belief is now challenged. Until now there has
been little evidence for native cardiac precursor cells in the postnatal heart but a
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