CARDIOVASCULAR JOURNAL OF AFRICA • Vol 24, No 5, June 2013
190
AFRICA
en/). Cardiovascular disease is also prevalent in South Africa,
resulting in 195 deaths per day between 1997 and 2004 (http://
).
The major cause of heart failure is the death of cardiomyocytes,
where a typical large myocardial infarct (MI) kills around
one billion myocytes (one-quarter of the heart).
6
The current
treatments do not address the problem of the reduced pool of
cardiomyocytes but rather involve transplantation or insertion of
mechanical ventricular assist devices.
For many years, prevailing dogma insisted that the heart was
a static post-mitotic organ incapable of regeneration. While
heart tissue has shown a capacity to regenerate, there is intense
controversy over whether cardiomyocyte division plays a role
in regeneration. Some
in vivo
studies have shown evidence of
possible cardiomyoctye division, although they fail to agree
on the rate of cardiomyocyte turnover,
7,8
and have been heavily
criticised for their methodology.
9
Regardless, it is evident that
their possible ability to divide does not extend to repairing
extensively damaged heart tissue.
The heart has also been shown to harbour a compartment of
multi-potent cardiac stem cells and other progenitor cells that can
differentiate into myocytes and coronary vessels. Again, there
has been much controversy surrounding this discovery. Some
believe that new myocytes may arise from the de-differentiation
of mature myocytes back to their immature state, allowing them
to acquire an immature phenotype and therefore to divide.
10
There are those that query whether the identified cardiac stem
cell population is fully distinct from haematopoetic stem cells
(HSCs) in the bone marrow, as these cells are able to enter the
circulation, home to organs and trans-differentiate, acquiring a
myocyte lineage.
11
This was initially a surprising finding as only
embryonic stem cells are pluripotent, and as they contribute to
the development of tissues, their potency becomes more and
more restricted to cells of that tissue.
It is thought that commitment to a developmental fate is
irreversible but plasticity has been shown, particularly with
HSCs. This line of thought has been heavily criticised, with
studies showing that HSCs cannot trans-differentiate into
cardiomyocytes after MI.
12,13
The existence of a c-kit
+
population of cardiac stem cells
able to self-renew and to differentiate into cardiomyocytes,
smooth muscle and endothelial cells has been demonstrated.
14
Detractors argue against the existence of these cells, reasoning
that spontaneous repair after injury does not occur. However,
stem cell niches have been described in many organs and while
these cells have been shown to play a role in regulating tissue
homeostasis, many do not effectively respond to aging or injury,
possibly because the adult environment is not permissible.
Keymessage:
Several experimental options to induce regeneration
of damaged heart tissue require investigation: activation of the
endogenous populations of cardiomyocytes and/or stem cells,
or the addition of exogenous cell-based therapy to replace lost
cardiac tissue.
Exogenous cell-based therapy: the different
types of stem cells used in clinical trials for
heart regeneration after injury
There are currently 30 to 40 registered clinical trials using different
types of stem cells to treat various types of cardiovascular disease
(
;
15
).
The overwhelming majority of the registered trials, completed,
on-going or not yet recruiting, involve the use of stem cells
derived from the bone marrow. The bone marrow is an attractive
source of stem cells as the cells can be obtained relatively easily.
The bone marrow contains a hetergoneous population of stem
cells of various lineages (including the blood mononuclear cells,
B-cells, T-cells and monocytes, as well as rare progenitor cells
such as haematopoietic stem cells, mesenchymal stem cells,
endothelial progenitor cells, CD
34
+
and CD
133
+
cells).
16
The bone marrow stem cell fraction can either be administered
whole or distinct bone marrow cell populations can be isolated
on the basis of specific cellular markers. Approximately half
the registered trials use whole bone marrow fractions while
the others use specific cells purified, using specific markers,
from the bone marrow fraction. These include bone marrow
mononuclear cells, bone marrow-derived mesenchymal stem
cells, endothelial cells, CD
34
+
and CD
133
+
cells.
Treatment with G-CSF (granulocyte colony-stimulating
factor) stimulates the movement of bone marrow stem cells into
the bloodstream and has been used in trials of patients suffering
from cardiovascular disease, either as the sole treatment to incite
movement of bone marrow stem cells into the bloodstream or in
conjunction with administration of stem cells. Trials have been
performed with both autologous and allogeneic bone marrow
stem cells. The majority of trials using bone marrow stem cells
use autologous bone marrow stem cells, whole or purified.
Although cardiac stem cells are more difficult to isolate,
as they can only be harvested from endomyocardial biopsies
and require careful growth conditions and identification using
markers such as c-kit, Sca-1 and Isl-1, trials have also been
performed with autologous cardiac stem cells. One of these trials
is slightly more complex and involves the addition of cardiac
stem cells along with a bFGF gel mat during coronary artery
bypass surgery for local release of bFGF.
17
As there are those
who are concerned about the ‘stemness’ of cardiac stem cells
(the ability of these cells to form cardiac tissue), there is a trial
using autologous cardiospheres. When cardiac stem cells derived
from biopsies are allowed to grow
in vitro
, the cells form spheres,
hence cardiospheres, and are presumably more committed to a
cardiac stem cell fate.
Key message:
Both bone marrow and cardiac-derived stem cells
have been used or are currently being used in clinical trials to
determine whether these cells could contribute to cardiac repair.
Does exogenous administration of autologous
or allogeneic stem cells aid in cardiac repair?
Results from randomised trials using bone marrow mononuclear
cells demonstrated modest cell therapy-mediated improvements
in ventricular function.
9
In one of the largest studies to date,
204 randomised patients diagnosed with acute MI received
intracoronary delivery of bone marrow cells or vehicle control.
After one year these patients showed significant improvements
in cardiac function.
18
A two-year follow up revealed that these
positive effects were preserved.
19
The authors showed experimentally that less than 20% of
the administered stem cells were retained in the heart,
20
which
indicates that some cells do home in on the target tissue, but
it also shows that only a few cells are needed to exert positive
