Jpg Sluijter

Stem cell therapy for end-stage heart failure: indispensable role for the cell?

Purpose of reviewFor heart failure patients, the urgent need for heart transplantation exceeds the availability of donor hearts. Therefore, cell transplantation has emerged as an interesting and potential solution. This review will focus on the capability of different types of stem cells to regenerate the heart. Moreover, the mechanism for success will be addressed, focusing on the specific (and indispensable?) role of the cells. Recent findingsIn recent years, many types of stem cells have been described as a possible source for cell transplantation in failing hearts, with mixed outcomes. Cell transplantation is hampered by suboptimal delivery techniques, limited survival of cells, and reduced proliferation and differentiation rates in vivo. Interestingly, the number of injected cells that engrafted the heart successfully cannot explain the observed beneficial effects and, therefore, paracrine effects are suggested for the success in cell therapy. SummaryThis review summarizes the current types of stem or progenitor cells used in cardiac cell therapy and beneficial effects on heart function and morphology in preclinical studies. Currently, the observed effects suggest that paracrine effects might be responsible, thereby triggering mobilization and activation of resident (stem) cells, which challenges the classical concept and true regenerative capacity of cell therapy at this point.

Suppression of T cells by mesenchymal and cardiac progenitor cells is partly mediated via extracellular vesicles

Adverse remodeling after myocardial infarction (MI) is strongly influenced by T cells. Stem cell therapy after MI, using mesenchymal stem cells (MSC) or cardiomyocyte progenitor cells (CMPC), improved cardiac function, despite low cell retention and limited differentiation. As MSC secrete many factors affecting T cell proliferation and function, we hypothesized the immune response could be affected as one of the targets of stem cell therapy. Therefore, we studied the immunosuppressive properties of human BM-MSC and CMPC and their extracellular vesicles (EVs) in co-culture with activated T cells. Proliferation of T cells, measured by carboxyfluorescein succinimidyl ester dilution, was significantly reduced in the presence of BM-MSC and CMPC. The inflammatory cytokine panel of the T cells in co-culture, measured by Luminex assay, changed, with strong downregulation of IFN-gamma and TNF-alpha. The effect on proliferation was observed in both direct cell contact and transwell co-culture systems. Transfer of conditioned medium to unrelated T cells abrogated proliferation in these cells. EVs isolated from the conditioned medium of BM-MSC and CMPC prevented T cell proliferation in a dose-dependent fashion. Progenitor cells presence induces up- and downregulation of multiple previously unreported pathways in T cells. In conclusion, both BM-MSC and CMPC have a strong capacity for in vitro immunosuppression. This effect is mediated by paracrine factors, such as extracellular vesicles. Besides proliferation, many additional pathways are influenced by both BM-MSC and CMPC.

Cellular Therapy for the Infarcted Myocardium

Heart failure is one of the leading causes of cardiovascular death, since no curative therapies are available yet. Heart failure is a progressive disease, of which myocardial infarction is one of the potential initiators, leading to a great loss of cardiomyocytes that are replaced by fibrotic tissue. As the endogenous regenerative capacity of the heart is inadequate to fully repair injured myocardium, cell-based therapy has been suggested as a promising treatment to improve cardiac performance. Multiple stem cell types, varying in source, mechanism of action, and potential effect, have been shown to improve cardiac function, although the exact mechanism responsible for this improvement (for example, differentiation of injected cells, activation of endogenous cell populations, or cellular fusion) is still unclear. Furthermore, all the cell types proposed to be used in cell therapy face major challenges that require extensive research. These challenges include the safety and method of cell delivery, cell survival in the harsh environment of infarcted tissue, including the inflammatory and fibrotic areas, transplanted cell proliferation and differentiation, potential for tumorigenesis, the formation of functional blood vessels, electromechanical integration, and long-term engraftment and stability. In this chapter, we will give an overview of current insights into cellular therapy of the infarcted myocardium and discuss the challenges that have to be faced if such therapies are to be used successfully in a clinical setting.