Mesenchymal stromal cells to treat cardiovascular disease: strategies to improve survival and therapeutic results

Following myocardial infarction, damage due to ischemia potentially leads to heart failure. Stem cell transplantation has emerged as a potential treatment to repair the injured heart, due to the inherent characteristics of stem cells such as self-renewal, unlimited capacity for proliferation and ability to differentiate to various cell lineages. Most promising results have been reported thus far on mesenchymal stem cells (MSC). Following transplantation in the heart, stem cells are expected to 1) reduce the damage; 2) activate the endogenous regenerative potential of the heart; and 3) participate in the regeneration of the tissue. Until now, the results of intervention with stem cells in animals were promising, but clinical studies have failed to live up to those expectations. Current problems limiting the efficacy of cellular therapy are: 1) limited knowledge on the time and mode of administration; 2) loss of homing receptors on culture-expanded cells as a consequence of the culture conditions; 3) massive cell death in the transplanted graft in the damaged heart, due to the hostile environment, 4) lack of knowledge on MSC behaviour in the heart. Since generally only 1-5% of delivered cells were found to actually engraft within the infarct zone, there is an urgent need for improvement. In animal models, strategies to precondition MSC before transplantation to survive in the damaged heart were applied successfully. These include exposure of cells to physical treatments (hypoxia and heat shock), pharmacological agents, "priming" of cells with growth factors, and genetic modification by over-expression of anti-apoptotic proteins, growth factors or pro-survival genes. To develop the strategy with maximal engraftment, survival and function of cells in the heart is the ultimate challenge for years to come.