Disclosure br In this issue of Premer et al

Disclosure
In this issue of , Premer et al. report their study titled “Allogeneic Mesenchymal Stem Cells Restore Endothelial Function in Heart Failure by Stimulating Endothelial Progenitor Cells” (). They recruited a cohort of heart failure patients from two ongoing clinical trials evaluating both autologous and allogeneic mesenchymal stem cell therapies and evaluated both molecular and functional markers of endothelial progenitor cell activity, showing significantly different outcomes between the allogeneic MSC recipients and the autologous MSC recipients. Mechanistically, Premer et al. show that MSCs can improve flow mediated vasodilation in their cohorts of patient while reducing the circulating VEGF to normal levels and increasing circulating endothelial progenitors. Mesenchymal Stem Cells (MSCs) were first reported by Friedenstein et al. in 1970 (). The finding that these MLN0128 could be induced to undergo cardiomyogenesis () stimulated great excitement regarding their cardiac regenerative capacity as a treatment for ischemic cardiomyopathy, and more recently for dilated cardiomyopathy. In fact, it could be argued that these discoveries catalyzed the proliferation of reports exploring the benefits of cell therapies, in-vitro, in animal models of heart failure and in clinical trials. This effect on the biomedical community can be illustrated by , which shows results from PubMed and Grants.gov searches several key words. While these searches are not exhaustive, it clearly shows that we have experienced a rapid growing interest in the potential of stem cells to 1.) improve clinical outcomes for heart failure patients, 2.) improve cardiac performance and reverse cardiac remodeling in these patients and 3.) regenerate lost myocardium, especially cardiomyocytes. Our ability to show each of these effects is relatively diverse. While testing for improved clinical outcomes with quality of life, imaging and hemodynamic endpoints is relatively straightforward, the degree of cardiac regeneration has been very challenging and inconsistent. Furthermore, the optimistic outcomes reported in pre-clinical studies have not been realized in clinical trials. This is partially due to the undetermined mechanism of action at the molecular, cellular and organ levels. As we have progressed through the first decade and a half of MCS cell therapy studies, their safety has been clearly demonstrated and the use of allogeneic vs autologous sources are being explored in detail (). It is becoming increasingly clear that several progenitor cell types including MSCs re-vascularize the damage heart muscle. In addition, the emphasis on the potential paracrine effects of MSCs in the heart () is emerging as a likely mode of action. From the more classical viewpoint, this involves cellular (such as MSCs) release of factors, including small proteins and growth factors, to either neighboring or remote cell types. These factors can be ligands of key receptor tyrosine kinases including vascular endothelial growth factor (VEGF) that bind to cell surface receptors such as VEGF receptors on endothelial cells. The cohort of patients in this study was recruited from the TRansendocardial Stem Cell Injection Delivery Effects on Neomyogenesis STudy (TRIDENT) in ischemic cardiomyopathy patients as well as the PercutaneOus StEm Cell Injection Delivery Effects on Neomyogenesis in Dilated CardioMyopathy (POSEIDON-DM) study. While data are available from the POSEIDON-PILOT study () evaluating a cohort of patients with ischemic cardiomyopathy, the POSEIDON-DCM and TRIDENT study results are not yet available. In the POSEIDON-PILOT study, no significantly different outcomes were noted between allogenic and autologous MSC recipients. It should be noted that there was no placebo control in the POSEIDON-PILOT study, so efficacy cannot be rigorously tested. MSCs have been reported to be immunoprivileged and immunosuppressive, because they do not express major histocompatibility class II antigens and they secrete T helper type 2 cytokines (). Therefore, the potential benefits of allogenic cell include use as an “off-the-shelf” therapeutic, thus avoiding the necessity for additional procedures for patients and delays in therapy. In addition, cell quality and selection could be much more highly controlled. There are also some concerns that autologous MSCs could be impaired in patients with comorbidities or advanced age.