CARDIOVASCULAR JOURNAL OF AFRICA • Vol 24, No 5, June 2013
192
AFRICA
These initial studies in animal models are promising,
however re-programming involves using viruses to introduce
the pluripotency factors into the cells, creating concerns. The
elimination of the need for viruses to re-programme the cells
would make iPS cells a very attractive option for the generation
of cardiomyocytes.
Another option is simply to skip the induction of pluripotency
and directly re-programme somatic cells into functional
cardiomyocytes. Research has shown that cardiomyocyte-
like cells can be derived from directly re-programming post-
natal dermal or cardiac fibroblasts, using three developmental
transcription factors:
Gata4, Mef2c
and
Tbx5.
33
Indeed, these
cells have been shown in mouse models of MI to contribute to
decrease in infarct size. As with the iPS cells, however, the use
of viruses to re-programme the cells still prevents translation into
clinical trials.
While all of these options are possible if the procedures
are made virus free, perhaps the simplest option would be to
circumvent cell-based therapy. All the clinical trial evidence
thus far points to the fact that the stem cells create a permissible
environment via paracrine signalling that serves to amplify
the endogenous regenerative response and/or stimulate cell
cycle re-entry of endogenous cardiomyocytes. Adult stem cells,
particularly mesenchymal stem cells, have been shown to
secrete a wide variety of factors that promote protection of the
myocardia, neovascularisation, cardiac remodelling, and improve
contractility.
34
The use of these molecules alone as a treatment to
stimulate endogenous cardiac repair is an exciting and promising
avenue of research.
Key message:
Cardiomyocytes can be synthetically created
from ES, iPS or even by simple trans-differentiation of somatic
cells using developmental cues. However, the creation of these
cells involves the use of viruses, which pose a risk to patients.
Paracrine factors are postulated to contribute to the positive
results seen in clinical trials. Identification of the secreted
molecules could pave the way for cell-free mechanisms of
stimulating the endogenous repair mechanism.
Conclusions
There are numerous on-going or completed clinical trials to
assess the abilities of bone marrow or cardiac-derived stem
cells to regenerate cardiac tissue destroyed by cardiovascular
disease. These trials have been shown to have limited success.
It appears that, although the initial aims of these trials were that
the exogenous stem cells would directly contribute to cardiac
repair by integrating into the target tissue, proliferating and
differentiating into cardiac-associated cell types, the positive
action exerted by these cells may be indirect.
It is believed that stem cells secrete various growth factors,
cytokines and signalling molecules that stimulate the endogenous
stem cells or cardiomyocytes to proliferate. The inability of the
exogenously administered stem cells to contribute directly may
be due to their lack of potency. It is therefore thought that,
to regenerate substantial cardiac tissue, either synthetically
generated stem cells such as iPS or directly re-programmed
somatic cells (generated without the use of viral vectors) are a
more feasible, though expensive, option.
It is clear that understanding of the molecules that direct heart
development and the environment in which the heart develops,
and the use of this information in creating new treatments is
essential. The development of a ‘cell-free’ treatment with the
administration of molecules that either stimulate the endogenous
cardiomyocytes, or stem cells to divide, or molecules that create
a permissive environment to stimulate regeneration would be an
ideal solution, eliminating the need for surgery.
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