Cardiovascular disease is the leading cause of mortality and morbidity in the US and worldwide. Cardiovascular disease, mainly due to myocardial infarction (MI) and its fatal consequences, heart failure and sudden cardiac death, places an enormous psychological and financial burden on patients, their families, and society. Over the past half-century, conventional medicine and surgery have made many advances that have led to a dramatic decrease in CV mortality. Disease process, the only definitive cure is a heart transplant.
Immunomodulatory properties of MSCs
MSCs are potent immune system modulators by suppressing white blood cells and triggering anti-inflammatory subgroups. Because MSCs inhibit T-cell proliferation in vitro, MSCs have been used to treat severe, drug-resistant graft-versus-host disease. The success of MSCs has led to intensive investigation of their immunomodulatory abilities. Furthermore, in addition to immunosuppressive properties, immunomodulatory properties underlie the ability of MSCs to be used as an allograft.
In Vivo Mechanism of Action
A significant accumulation of data from clinical, preclinical, and in vitro settings supports a multifactorial mechanism of action for the cardioreparative effects of MSCs. Three main mechanisms of action underlie the beneficial effects of MSCs in disease: 1) reduction in fibrosis, 2) stimulation of angiogenesis, 3) restoration of contractile function through engraftment, differentiation, and stimulation of endogenous cardiac stem cells to proliferate and differentiate perfused tissue.
Many early studies showed that reduced apoptotic myocytes and increased vascularity characterized the border zone of experimentally induced myocardial infarction. Scar tissue reduction and cardioprotection after MSC transplantation are well described in both preclinical models and clinical trials. Amado et al. demonstrated myocardial tissue recurrence and contractility restoration after MSC implantation in pigs using in vivo serial CT imaging.
New vessel formation is the cornerstone of any significant cardiac repair. There are three mechanisms of postnatal neovascularization: 1) angiogenesis, 2) arteriogenesis, and 3) postnatal vasculogenesis, in which endothelial progenitors derived from the OM assemble to form new blood vessels. It is still debated whether the observed increase in capillary density and tissue perfusion is due to the differentiation of MSCs into endothelial cells and vascular smooth muscle cells or to the secretion of paracrine mediators and the formation of new pericytes. There is evidence that MSCs function as pericytes, perivascular cells essential for vascularization by stimulating endothelial cells to form tubular structures and, subsequently, vascular networks.
Direct MSC stimulation of endogenous repair
Several groups have now shown that MSC transplantation stimulates the proliferation and differentiation of endogenous cardiac stem cells. This discovery provides a very plausible explanation for the replacement of scar tissue by new contractile myocardium. Neomyogenesis occurs by stimulating endogenous cardiac stem cells (c-kit+ and other lineages) and amplifying the myocyte cell cycle. In the first demonstration of this phenomenon, allogeneic GFP+-MSCs were injected into the hearts of infarcted pigs and formed chimeric clusters containing immature MSCs and endogenous ckit+ cardiac stem cells.
The groups demonstrated connexin-43-mediated gap junction-mediated cell-cell interactions and N-cadherin-mechanistic connections.
Safety of MSCs therapy:
Although the large body of preclinical and clinical data suggests that MSCs have great potential in the treatment of heart disease, and despite all the evidence supporting the safety of MSC transplantation, it is essential to note that the same long-term protection required is learning. There are two major theoretical concerns regarding MSC therapy, arrhythmogenicity and tumorigenicity. As discussed above, the former has proven unproblematic in all completed clinical studies.
Future Directions for MSCs:
There is now a large body of evidence from preclinical and early clinical studies clarifying the mechanism of action and uncovering potential pitfalls of MSC therapy. It is also well recognized that one of the significant limitations to the long-term efficacy of MSC therapy is the poor retention and survival of the transplanted cells.