Myocardial infarction (MI) is characterised by the irreversible death of cardiac muscle with
loss of up to 1 billion cardiomyocytes (CM). Despite survival post-MI dramatically improving
in the last two decades, more than 20% of patients suffering MI will still develop heart failure
(HF), an incurable condition where the heart is no longer able to meet the body’s needs for
blood supply. Amongst novel therapeutic avenues currently being explored, intramyocardial
delivery of cardiomyocytes derived from human induced pluripotent stem cells (hiPSC-CMs)
holds great promise to replace the lost functional tissue. However, the effects of the ischemic
microenvironment on these cells still need to be investigated, and protective strategies need
to be developed. This thesis examines the delivery of the pro-survival growth factor Insulin
like Growth Factor-1 (IGF-1) in the settings of hiPSC-CMs exposed to acidic pH and through
a hydrogel-based approach in an in vivo model of MI.
Following MI, the heart switches from aerobic metabolism to anaerobic glycolysis, causing a
pH drop to 6.5-6.8. The aim of the first part of this thesis was to mitigate the effects of acidic
pH on hiPSC-CMs using the pro-survival growth factor IGF-1. It was shown that acidic pH
negatively affects hiPSC-CMs in terms of viability, metabolic activity, cardiac gene expression
and CMs yield obtained through differentiation. IGF-1 was able to recover the effects of acidic
pH, and it could, therefore, be used as a protective strategy for in vivo cell therapy approaches.
Another promising strategy for preventing HF progression following MI is the minimally
invasive delivery of injectable hydrogels, which can provide mechanical support to damaged
tissue and deliver bioactive factors with pro-survival actions. Here, a thermoresponsive
injectable hydrogel composed of a triblock copolymer of polyethylene glycol (PEG) and
polycaprolactone (PCL) was synthesised and characterised in vitro and in vivo. The hydrogel
was prepared with or without insulin-like growth factor-1 (IGF-1) and injected
intramyocardially in a mouse MI model. Echocardiography, strain analysis and histological
assessments showed that the injection of the biodegradable thermoresponsive hydrogel was
effective in ameliorating pathological remodelling, improving overall cardiac function and
myocardial mechanics. In the future, implementing novel therapeutic approaches like the
ones presented in this thesis could prevent the progression to HF, improving the quality of
life of patients affected by myocardial infarction and limiting the socio-economic burden of
the disease.