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7.4 Animal Studies with CSCs
A plethora of studies have demonstrated that isolated and culture-expanded c-kit+/
Lin− CSCs exhibit all the properties of bonafide stem cells, and when injected into
the injured myocardium, are capable of restoring (to a variable extent) the cardiac
structure and function in various animal models. Several parameters such as infarct
size, left ventricular ejection fraction (LVEF), LV volumes, cardiac output, LV seg-
mental wall thickening and ventricular remodeling have been assessed as critical
end-points after CSC therapy. Studies indicate that the administration of CSCs can
slow left ventricular remodeling and improve cardiac function in both acute and
chronic models of MI. In the first report on CSCs, Beltrami et al. [ 1 ] injected 1 × 10^5
culture expanded ckit-pos cells into the hearts of syngeneic rats acutely after myo-
cardial infarction (5 h old infarcts) and reported that CSCs regenerate more than
50% of the contractile myocytes and vascular cells normally present in the myocar-
dium [ 1 ]. Dawn et al. [ 27 ] performed an intravascular delivery of rat CSCs in a
clinically relevant rat model comprising of temporary coronary occlusion followed
by reperfusion. CSCs induced myocardial regeneration and decreased infarct size
by 29%. Further, the study indicated that cell fusion did not contribute to tissue
reconstitution [ 27 ]. Bearzi et al. [ 28 ] injected human CSCs in the immunodeficient
mouse or imunocompromised infracted rat heart to form chimeric organs containing
human myocytes and coronary vessels. The hCSCs differentiated into human myo-
cytes and coronary vessels, leading to the formation of a chimeric heart in the recip-
ient animals. Further, the human myocardium structurally and functionally
integrated with the rodent myocardium and contributed to the performance of the
infarcted heart. This study also ruled out any possibility of cell fusion between
human CSCs and rodent cells [ 28 ].
Tang et al. [ 29 ] infused GFP-tagged CSCs in rats one month after coronary
occlusion/reperfusion injury via intracoronary route. At 5 weeks post- transplantation,
CSC-treated hearts exhibited improvements in both LV structure and function, as
demonstrated by greater viable myocardium in the risk region, less fibrosis in the
non-infarcted region, and improved ejection fraction (EF) in comparison to the
vehicle controls [ 29 ]. Bolli et al., demonstrated that an intracoronary administration
of autologous CSCs to a swine model of chronic ischemic cardiomyopathy resulted
in a significant increase in LV function, indicated by an increase in EF and systolic
thickening fraction in the infarcted LV wall, as well as a decrease in LV end- diastolic
pressure one month post-infusion. The study also demonstrated using GFP-labeled
CSCs that newly cardiomyocytes and vascular structures were derived from the
transplanted cells [ 30 ]. In another similar study, Welt et al. [ 31 ] used a canine model
of chronic infarction and late adverse ventricular remodeling and demonstrated that
after six weeks of coronary ligation, intramyocardial injection of autologous CSCs
resulted in significant improvement in LV volumes and LVEF compared with con-
trols even at 30 weeks post-infarction, indicating that CSCs also have a beneficial
effect on the late phase of cardiac remodeling in the chronically infarcted canine
heart.
S. Kaur et al.