Human cardiac stem cell therapy has been introduced into the clinical practice a decade ago, based on the promising results of in vitro and in vivo small animal experiments. Several mechanisms have been proposed to explain the expected mode of action, such as transdifferentiation, cell fusion or paracrine effect.
After lot of small pilot studies, large phase II mainly randomized clinical studies have been started, such as the study of Strauer, the REPAIR-AMI, LEUVEN-AMI, ASTAMI, REGENT, HEBE and the BOOST studies for patients with recent acute myocardial infarction (AMI), and MAGIC, TOPCARE-CHD and MYSTAR studies for patients with ischemic cardiomyopathy. Currently, several trials are on-going, such as the continuation of previous trials, or PROMETHEUS or the C-cure studies.
However, the initial enthusiasm has been broken showing the only moderate (up to 4-6%) improvement in ejection fraction and decrease in infarct size, indicating, that the achieved marginal and sometimes transient significant benefit is rather statistical, than clinical, concluding that the currently available stem cells and culture and delivery techniques are unable to achieve a clinical relevant (robust) myocardial tissue regeneration in humans. The disappointing clinical experiences have triggered searching of new stem cell types (eg. cardiospheres, induced pluripotent stem cells), improving the existing techniques (eg. combination of cell types, or deliveries), modification of the stem cells mechanically (eg. survival coctails) or genetically (eg. plasmids for growth factor expression), or developing tissue engineering.
Additionally, it became clear, that we need to go back to bench side, and perform large animal experiments with closed chest reperfused AMI, because this is the only relevant model of human reperfused infarction (e.g. primary PCI for AMI) and ischemic cardiomyopathy regarding cell dosing, delivery and types. The recognition of the migration and destination of the cardially injected stem cells in remote organs raised several safety concerns, therefore new in vitro and in vivo cell tracking methods have been developed. Genomics and proteomics analyses are currently performed to explore the gene and protein expression of the injected cells and the host tissue.
Currently, among intensive research on experimental and clinical myocardial regeneration therapies, research focuses on new directions, such as the exploitation of the paracrine effect of the cardially injected living or apoptotic stem cells, which triggers the expression of several angiogenic and growth factors and reparative cytokines during hypoxic burden of the myocardium, mimicking ischemic preconditioning of the heart. New substrates are under investigation, facilitating homing and recruiting of the stem cells; confirming the hypothesis of the human endogenous cardiac repair.