CARDIOVASCULAR JOURNAL OF AFRICA • Vol 24, No 5, June 2013
AFRICA
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effects. These results are in contrast to those obtained by a
similarly constructed study where patients suffering from acute
ST-segment elevation MI were administered bone marrow-
derived stem cells. While initial results were promising,
21
the
18-month and five-year follow ups have shown that, while the
treatment had an overall positive effect, this was attributed to the
early improvement, with little sustained effect seen.
22
The general consensus is that bone marrow stem cell treatment
moderately improves heart function, does not decrease mortality
or morbidity significantly in long-term follow up, and has, as
yet, not been associated with any significant safety concerns.
23
How these cells act to repair the damaged tissue is not known.
Some believe that the bone marrow cells trans-differentiate
into cardiomyocytes.
10
However, it is generally believed that
these cells secrete paracrine factors, creating a permissible
environment, which stimulates the endogenous cardiomyocyte
progenitor cells or adult cardiomyocytes to divide. While this is
entirely probable, there is little evidence for this.
Similarly, trials using selected cell populations such as
endothelial progenitor cells (which promote angiogenesis and
possibly secrete paracrine factors thatmaypromote cardiomyocyte
division) or mesenchymal stem cells (which can differentiate
into cardiomyocytes although the rate of differentiation is low)
isolated from bone marrow have shown similar results to the
whole bone marrow fraction studies described.
9
One of the first trials, the Stem Cell Infusion in Patients
with Ischemic cardiOmyopathy or SCIPIO trial, using purified
cardiac stem cells, has recently produced interim results. In
this study, autologous c-kit
+
cells were isolated and grown from
tissue harvested during coronary artery bypass surgery, and
administered to the patient at a later stage by intracoronary
infusion. Cardiac magnetic resonance showed that, not only is
the procedure feasible, but also that administration of the cells
produced a striking improvement in both global and regional
left ventricular function, a reduction in infarct size, and an
increase in viable tissue, which persisted at least one year after
administration, consistent with cardiac regeneration.
24,25
Initial results from the CADUCEUS (CArdiosphere-Derived
aUtologous stem CElls to reverse ventricUlar dySfunction)
randomised, controlled trial have also been released. Here,
after myocardial infarction, autologous cardiac stem cells were
isolated from endomyocardial biopsy specimens and allowed
to grow
in vitro
to form cardiospheres. These were then
administered via intracoronary delivery. Initial results indicate
that the process is safe and viable, and showed a decrease in scar
tissue mass after MI, and regeneration of viable myocardium.
26
It is possible that the positive results of the cardiac stem cells
and cardiosphere trials are not due to direct stem cell action,
27
as
the cardiac ‘stemness’ of cardiac stem cells and cardiospheres
has been questioned. Using an elegant labelling technique where
transgenic mice were generated with enhanced green fluorescent
protein under the control of the c-kit gene promoter, a report
showed that, while c-kit marks cardiac progenitor cells during
development, in the adult, it is not a marker for cells capable
of cardiomyogenesis. This study shows that, at least in this
experimental model, cardiac c-kit
+
cells
28
and cardiospehere-
derived cells lack cardiomyogenic potential.
29
All of these described trials were designed with the intent
that the stem cells, whether bone marrow or cardiac derived,
engraft into the diseased tissue and differentiate into functional
cardiomyocytes. However, the results suggest that it is not that
simple and that the modest improvements seen are probably
due to the exogenous cells creating a permissible environment
(by secreting factors and appropriate signals) that induces the
endogenous cardiomyocytes or cardiac stem cells to proliferate.
It is therefore suggested that basic knowledge of stem cell and
developmental biology be exploited to further increase the
positive effects seen thus far.
30
Key message:
Bone marrow or cardiac-derived stem cells do
contribute to cardiac repair or survival, however, it seems that
these cells do not contribute directly. Their action appears to
be effected by paracrine secretions, which create a permissible
environment for the endogenous repair mechanisms.
Exploitation of developmental and stem cell
biology knowledge
The clinical trials described so far have had only marginal, if any,
success. This may be due to the use of adult stem cells that lack
the necessary plasticity to differentiate into cardiomyocytes. It
may be that more highly plastic cells are needed to recapitulate
cardiomyogenesis. In theory, this requirement should be satisfied
by the use of cardiac stem cells, cells that should be able to
differentiate into cardiomyocytes. However, it appears that they
may not persist into adulthood or may express different markers
in the adult. Their use is also complicated by the fact that
autologous cardiac stem cells are harvested after damage to the
heart and, generally, from older patients.
The most plastic or potent cells are ES cells. ES cells were
first isolated from a human embryo in 1998 and since then,
several ES cell lines have been created, which perpetuate in
culture. These cells cannot simply be administered to patients,
as their intrinsic potency and ability to divide causes teratomas,
even several years after therapeutic delivery.
These issues can be overcome by directing human ES cells
along a pathway of differentiation towards a cardiomyocyte
lineage. Various recipes involving sequential exposure to BMP2,
FGF andWnt, and BMP inhibitors as in normal heart development
have been shown to generate cells with the potential to form
cardiomyocytes, smooth muscle and endothelial cells. When
transplanted into primates, these cells did not form teratomas
but contributed to the repair of scar tissue. The rationale
behind this basic work is to generate a pool of pure ES-derived
cardiomyocytes, which could be used for ‘off-the-shelf’ therapy.
31
This is a clever but very expensive approach that is still muddied
by the initial use of ethically controversial ES cells.
Induced pluripotent stem (iPS) cells are adult, somatic cells
which have been re-programmed by the addition of three or four
embryonic transcription factors to become pluripotent. These
cells overcome the ethical concerns created by embryonic stem
cells and also graft rejection, as they can be engineered from a
patient’s own stromal cells for autologous transplantation.
Mouse embryonic fibroblasts were induced to become
pluripotent by forced expression of the pluripotency markers,
OCT3/4, SOX2, KLF4 and c-MYC. These iPS cells were
administered to athymic nude mice after the induction of
myocardial ischaemia by left coronary artery ligation. These
cells did not form tumours and successfully integrated into
the allogeneic host heart parenchyma, contributing to tissue
reconstruction with synchronised cardiovasculogenesis.
32
