Transplantation of Genetically Engineered Cardiac Fibroblasts Producing Recombinant Human Erythropoietin to Repair the Infarcted Myocardium - Genetic Engineering: Recent Developments in Applications - page 201

discussion
To the best of our knowledge, the present study is the first to use reprogrammed
cardiac fibroblasts encoding the rhEPO gene to repair infarcted myocardium in
situ. In previous experiments, rhEPO was delivered systemically prior to, at dif-
ferent time points and immediately after ischemia/reperfusion or cardiomyopathy
induction [27-30]. In our study, rhEPO produced from genetically modified car-
diac fibroblasts exhibited a strong anti-apoptotic effect in vitro, promoted angio-
genesis and attenuated apoptosis in the infarcted tissue. However, despite positive
in vitro results and cytoprotection of EPO-transduced cells in the infarcted hearts,
restoration of LV function was not observed, and there was a trend to more ad-
verse remodeling.
Cardiac fibroblasts present an attractive gene carrier into the infarcted heart.
Although not an 'ideal' source for transplantation (due to lack of contractility and
so on), fibroblasts, constituting the major cell population of the myocardium,
can be easily obtained from clinically accessible sites, expanded in vitro without
significant limitation, and, unlike cardiomyocytes, can be transduced highly ef-
ficiently by retroviral EPO-based gene transfer.
Our findings concur with other studies that show a lack of functional im-
provement following EPO treatment despite positive cellular effects (apoptosis
inhibition and angiogenesis) [31-35], as well as one clinical trial conducted with
EPO analogue darbepoetin alfa [36].
The reason for the inconsistency between the cytoprotective effect of EPO
in vitro and in situ versus the lack of functional improvement in vivo is unclear.
A possible explanation is that an EPO therapeutic effect on LV remodeling and
function is mainly mediated by endothelial progenitor cell recruitment, which is
achieved by systemic administration [34,37,38]. This notion is supported by the
positive correlation found between EPO plasma levels and endothelial progenitor
cell recruitment in an observational study of patients after acute MI [39]. Thus,
local EPO therapy is insufficient for functional improvement.
In addition, the lack of improvement could be related to the timing of therapy.
In most of the positive EPO studies systemic cytokine administration was initi-
ated before or immediately after ischemia/reperfusion induction. We used a more
severely injured model with more clinically relevant timing of cell delivery (1
week post MI). However, at this stage, EPO could be less effective due to a rela-
tively low cell apoptotic rate and the lack of stem cell homing signals from the
infarct [35].