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28% and 46% at 6 and 12 months respectively. Also, no complications were reported
within 6 months of CDC infusion. Further, a 1 year follow up of the CADUCEUS
trial patients was performed [ 35 ]. MRI revealed that CDC-treated patients had
smaller scar size compared with control patients and the scar mass decreased and
viable mass increased in CDC-treated patients but not in control patients. Also, the
changes in left ventricular ejection fraction in CDC-treated subjects were consistent
with the natural relationship between scar size and ejection fraction post-MI.
Since autologous therapy is associated with significant technical, timing, eco-
nomic and logistic limitations, researchers have now started exploring the potential
of allogeneic CDC therapy. CDCs exhibit a favorable immunologic antigenic profile
and are hypoimmunogenic in vitro. Hence, allogeneic human CDCs are currently
being tested clinically in the ALLSTAR and DYNAMIC trials [ 36 ]. Another small
phase-1 trial, ALCADIA (AutoLogous Human CArdiac-Derived Stem Cell To
Treat Ischemic cArdiomyopathy) administrated autologous CDCs together with a
controlled release formulation of basic Fibroblast Growth Factor (bFGF) in six
patients with ischemic cardiomyopathy and heart failure. At 6 months, four patients
showed an increase in LVEF and infarct size decreased by 3.3% of the total LV
volume and maximal aerobic exercise capacity increased. The results of the trial
were however not published, owing to small sample size [ 37 ].
Although the initial results of the trials are promising, CSC therapy is still in its
infancy. This may be ascribed to various impediments, including, small numbers of
CSCs that can be isolated from biopsies, limited numbers available for transplanta-
tion and poor survival and retention of the injected cells in the heart. Thus, increas-
ing survival and retention of the transplanted CSCs in the heart currently constitutes
one of the major challenges in the field of CSC therapy. In this regard, multiple
protocols have been developed to optimize the survival and expansion of both ex-
vivo transplanted and endogenous human c-kit-positive CSCs for clinical use.
7.6 Engineering of CSCs: Ex-Vivo Manipulation Studies
Since the isolation and identification of CSCs, multiple protocols have been devel-
oped to optimize the expansion of human c-kit-positive CSCs for therapeutic use
(Fig. 7.1). Various groups have generated multicellular clusters known as cardio-
spheres, which have yielded cardiosphere-derived cells (CDCs) cardiospheres from
human endomyocardial biopsy specimens. Human cardiospheres express c-Kit and
CD105, a regulatory component of the transforming growth factor-β receptor com-
plex important in angiogenesis and hematopoiesis [ 15 , 16 ]. Cells within the cardio-
sphere core are proliferative, as identified by Ki67 expression. Human and porcine
CDCs also differentiate into electrically functional myocytes in vitro and when
injected into mice, these CDCs also lead to myocardial regeneration and functional
improvement after infarction [ 16 ]. Gouman et al., have described efficient isolation
and propagation of human cardiomyocyte progenitor cells (hCMPCs) from fetal
heart and patient biopsies. Establishment of hCMPC cultures have been remarkably
S. Kaur et al.