Current Stem Cell Research & Therapy - Volume 8, Issue 4, 2013

The pandemic of cardiovascular disease is continuously expanding as the result of changing life styles and diets throughout the Old and New World. Immediate intervention therapy saves the lives of many patients after acute myocardial infarction (MI). However, for many this comes at the price of adverse cardiac remodeling and heart failure. Currently, no conventional therapy can prevent the negative aftermath of MI and alternative treatments are warranted. Therefore, cardiac stem cell therapy has been put forward over the past decade, albeit with modest successes. Mesenchymal Stem Cells (MSC) are promising because these are genuine cellular factories of a host of secreted therapeutic factors. MSC are obtained from bone marrow or adipose tissue (ADSC). However, the heart itself also contains mesenchymal- like stem cells, though more difficult to acquire than ADSC. Interestingly, mesenchymal cells such as fibroblasts can be directly or indirectly reprogrammed to all myocardial cell types that require replacement after MI. To date, the paracrine and juxtacrine mechanisms of ADSC and other MSC on vessel formation are best understood. The preconditioning of, otherwise naive, stem cells is gaining more interest: previously presumed deleterious stimuli such as hypoxia and inflammation, i.e. causes of myocardial damage, have the opposite effect on mesenchymal stem cells. MSC gain a higher therapeutic capacity under hypoxia and inflammatory conditions. In this review, mesenchymal stem cells and their working mechanisms are put into the perspective of clinical cardiac stem cell therapy.

Modern life styles have made cardiovascular disease the leading cause of morbidity and mortality worldwide. Although current treatments substantially ameliorate patients’ prognosis after MI, they cannot restore the affected tissue or entirely re-establish organ function. Therefore, the main goal of modern cardiology should be to design strategies to reduce myocardial necrosis and optimize cardiac repair following MI. Cell-based therapy was considered a novel and potentially new strategy in regenerative medicine; however, its clinical implementation has not yielded the expected results. Chemokines seem to increase the efficiency of cell-therapy and may represent a reliable method to be exploited in the future. This review surveys current knowledge of cell therapy and highlights key insights into the role of chemokines in stem cell engraftment in infarcted myocardium and their possible clinical implications.

Numerous studies have previously shown the efficiency of stem cell therapy in recovering the infarcted myocardium, by reducing the infarct size and improving the overall global function. However, the functional improvements observed in almost all cases were short-termed and many clinical trials showed that there were no long term relevant differences between infarcted myocardium with and without cell transplant. Moreover, studies monitoring cell engraftment after transplantation reported that cells were poorly retained into the heart and their large majority died posttransplantation, thus explaining the transient nature of the improvements. In these settings, it is likely that the improvement in the cardiac function is not due to the myocardial structure regeneration but rather to the biomolecules secreted by stem cells, which can improve the ventricular remodelling by attenuating the inflammation and promoting vascularisation and cell survival. This conclusion has prompted a re-consideration of stem cell field and imposed the stringency of understanding how stem cells respond to the host environment and differentiate toward a specific cell phenotype. This review is focused on the behaviour of mesenchymal stem cells after transplantation into the myocardial infarction and the molecular changes appeared in the infarcted environment that complicate the cross-talk between transplanted and host cells.

The stem cell-based therapy for post-infarction myocardial regeneration has been introduced more than a decade ago, but the functional improvement obtained is limited due to the poor retention and short survival rate of transplanted cells into the damaged myocardium. More recently, the emerging nanotechnology concepts for advanced diagnostics and therapy provide promising opportunities of using stem cells for myocardial regeneration. In this paper will be provided an overview of the use of nanotechnology approaches in stem cell research for: 1) cell labeling to track the distribution of stem cells after transplantation, 2) nanoparticle-mediated gene delivery to stem cells to promote their homing, engraftment, survival and differentiation in the ischemic myocardium and 3) obtaining of bio-inspired materials to provide suitable myocardial scaffolds for delivery of stem cells or stem cell-derived factors.

Although the treatment of acute myocardial infarction has improved considerably and the mortality rate is reduced, patients who survive may develop loss of cardiomyocytes, scar formation, ventricular remodeling, and ultimately heart failure. The treatment of the most severe types of heart failure is heart transplantation, but this therapeutic intervention is not available for a large number of patients due to a shortage of donor hearts. Since current pharmacological and interventional approaches are unsuccessful to regenerate infarcted myocardium, new approaches like gene- or cell-based therapies are tested to prevent loss of cardiac tissue, enhance angiogenesis, and to reduce left ventricular remodeling. Exciting and promising data on laboratory animals have moved the field rapidly into clinical trials. Although several clinical trials proved the safety and feasibility of using gene- and cell-based therapies, many challenges remain before large-scale novel treatment modules will be available. The purpose of this review is to summarize the key findings of larger, randomized clinical trials in cardiovascular medicine using both gene and cell-based therapy, and to emphasize the most significant questions that emerged from the clinical experience so far, such as the optimal gene or cell type to be used, the ideal delivery route, and for DNA the ideal delivery system. Understanding the mechanisms of gene- and cell-based therapies is essential for designing the next phase clinical studies in the field of regenerative medicine.

Stem cells have the ability to self-renew and to differentiate into multiple mature cell types during early life and growth. Stem cells adhesion, proliferation, migration and differentiation are affected by biochemical, mechanical and physical surface properties of the surrounding matrix in which stem cells reside and stem cells can sensitively feel and respond to the microenvironment of this matrix. More and more researches have proven that three dimensional (3D) culture can reduce the gap between cell culture and physiological environment where cells always live in vivo. This review summarized recent findings on the studies of matrix mechanics that control stem cells (primarily mesenchymal stem cells (MSCs)) fate in 3D environment, including matrix stiffness and extracellular matrix (ECM) stiffness. Considering the exchange of oxygen and nutrients in 3D culture, the effect of fluid shear stress (FSS) on fate decision of stem cells was also discussed in detail. Further, the difference of MSCs response to matrix stiffness between two dimensional (2D) and 3D conditions was compared. Finally, the mechanism of mechanotransduction of stem cells activated by matrix mechanics and FSS in 3D culture was briefly pointed out.

Graft-versus-host disease (GvHD) remains the major barrier to successful allogeneic hematopoietic stem cell transplantation (HSCT). Extracorporeal photopheresis (ECP) is a potent immunomodulatory treatment option for GvHD. In contrast to conventional immunosuppressants, ECP is considered not to increase relapse and infection rates resulting from generalised immunosuppression. ECP involves the mechanical separation of 5-10% of patient peripheral blood mononuclear cells, which are then exposed to psoralen and UVA light (PUVA) before they are returned to the patient. ECP has been shown to induce apoptosis in various cell types, in particular lymphocytes. Several studies describe downregulation of pro-inflammatory cytokines as well as promotion of peripheral tolerance through enhanced production of Tregulatory cells in the course of ECP-treatment. Modulation of antigen-presenting cells such as dendritic cells (DC) by PUVA-treated lymphocytes might be implicated in these regulatory processes. We evaluated the impact of PUVA-treated lymphocytes on immature DC and further demonstrated the functional capacity of such modified DC to modulate GVH reactions using a well-established human skin-explant model of GvHD. Addition of immature DC isolated after co-culture with PUVA-treated but not untreated MLR cells significantly downregulated skin-GvH reactions (p=0.023, Mann-Whitney-Test). IFN-gamma levels were non-significantly decreased in MLR and skin supernatants. We observed a non-significant increase in PD-L1 expression in iDC after co-culture with PUVA-treated MLR cells whereas expression levels of IDO and ILT-3 were not affected. We conclude that iDC modulated by PUVA-induced apoptotic cells potently downregulate allogeneic immune responses possibly through PD-L1- dependent signaling.

Recent clinical studies have demonstrated the capacity of immunosuppressive therapy to delay progression of inflammatory insulitis in type 1 diabetes (T1D). The procedure includes depletion of pathogenic cells by immunosuppressive therapy and support of recovery by reinfusion of autologous hematopoietic progenitors. The short-term outcome of these clinical transplants is similar to the predictions drawn from NOD mice: debulking of diabetogenic cells is ineffectively achieved by immunosuppressive therapy, and resetting of immune homeostasis does not restrain autoimmunity. Murine models indicate that allogeneic transplants are potentially curative, through restored mechanisms of negative regulation that are effective in continuous and indefinite suppression of autoimmunity.