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Cardiac Stem Cell Therapy Comes Closer to Mainstream

Cell Transplantation, December 27, 2007

In the therapeutic efforts that have been directed at the treatment of a variety of cardiac disorders, a great deal of progress has been made in the understanding of this science since the year 2000. Many questions still remain and research directed at answering some of these questions was presented in the current issue of CELL TRANSPLANTATION (Vol.16 No. 9), The Proceedings of the Third Annual Conference on Cell Therapy for Cardiovascular Disease. The issue was comprised of eleven separate papers, four of which are sampled below.

Amit N. Patel, MD, MS, director of cardiac cell therapy at the University of Pittsburgh Medical Center and lead author of an overview and introductory article, Cardiac Stem Cell Therapy from Bench to Bedside, stated that “cardiac stem cell therapy involves delivering a variety of cells into hearts following myocardial infarction or chronic cardiomyopathy.”

He continued by saying that, “many questions remain, such as what types of cells may be most efficacious. Questions about dose, delivery method, and how to follow transplanted cells once they are in the body and questions about safety issues need answers. The following studies, contribute to the growing body of data that will move cell transplantation for heart patients closer to reality.”

The type of disease to be treated is what determines what source of cells for cardiac transplant will be most suitable said Patel, special editor for this issue. Cells that replace or promote myogenesis, reverse apoptopic mechanisms and the reactivation of dormant cell processes will be useful for heart failure. A cell that reduces myocardial necrosis and augments vascular blood flow will be desirable for acute myocardial infarction.

“Very little data is available to guide cell dosing in clinical studies,” says Patel. “Pre-clinical data suggests that there is a dose-dependent improvement in function.”

The availability of patient self-donated (autologous) cells may fall short notes Patel.

The issue of dose is presented when determining optimal delivery methods, but timing must be determined as well. “Critical to understanding mechanisms of action,” is the process of assessing the fate of the injected cells.

Labeling stem cells with durable markers to see if cells home to the site of injury will be necessary. Development of new tracking markers may also be required.

When delivered to heart tissues following a myocardial infarction (MI), adult bone marrow-derived mesenchymal stem cells (MSCs) have shown great signaling and regenerative properties. However, researchers have been concerned with the poor survival rate of grafted cells. Grafted cells survive with difficulty given an active inflammatory process and poor vascular supply after a heart attack. Oxygenated blood supply can be enhanced by a process called transmyocardial revascularization (TMR), a process by which channels are created in heart tissues by laser or other means.

“We hypothesized that using TMR as a scar pretreatment to cell therapy might improve the microenvironment to enhance cell retention and long-term graft success,” said Amit N. Patel, lead author of a study titled Improved Cell Survival in Infarcted Myocardium Using a Novel Combination Transmyocardial Laser and Cell Delivery System.

“TMR may act synergistically with signaling factors to have a more potent effect on myocardial remodeling.”

Significant cell survival was reported in the TMR+Cell group versus Cells or TMR alone. A novel delivery system to disperse cells in the TMR-generated channels in an animal model was used by Patel and colleagues. The survival of transplanted cells was possibly improved by an increase in local production of growth factors according to researchers.

Recent studies have suggested that there are stem cells in the heart. In this study, stromal cell-derived factor-1 (SDF-1), a chemokine, was overexpressed by mesenchymal stem cells which had been engineered by researchers.

“Our study suggests that the prolongation of SDF-1 expression at the time of an acute myocardial infarction (AMI) leads to the recruitment of what may be an endogenous stem cell in the heart,” says Marc Penn, MD, PhD, director of the Skirball Laboratory for Cardiovascular Cellular Therapeutics at the Cleveland Clinic Foundation. “These cells may contribute to increased contractile function even in their immature stage.”

Following an AMI that can be manipulated through the expression of key molecular pathways, researchers concluded that there is a natural but inefficient stem cell-based repair process in the study titled SDF-1 Recruits Cardiac Stem Cell Like Cells that Depolarize in Vivo. The mechanical and electrical functions of the surviving myocardium can be significantly impacted by the outcome of this inefficient repair.

Because of low cell retention and poor graft viability, cardiac cell transplantation has had limited success, despite improve ventricular function being the goal of cell transplantation. To help support and regenerate post-ischemic lesions, a matrix seeded with bone marrow cells (BMC) was grafted onto the infarcted ventricle by a team of researchers from the Department of Cardiovascular Surgery, Pompidou Hospital in this study.

“Our study demonstrated that bone marrow cell therapy associated with the surgical implantation onto the epicardium of a cell-seeded collagen type 1 matrix prevented myocardial wall thinning, limited post-ischemic remodeling and improved diastolic function,” says Juan Chachques, MD, PhD, lead author for Myocardial Assistance by Grafting a New Bioartificial Upgraded Myocardium (MAGNUM Clinical Trial): One year follow-up.

“The use of the biomaterial appears to create a micro atmosphere where both exogenous and endogenous cells find an optimal microenvironment to repair tissues and maintain low scar production,” explains Chachques.

Several mechanisms are responsible for the favorable effects according to Chachques. Through epicardial channels created at the injection sites the BMC seeded in the collagen matrix may be incorporated into the myocardium. Apoptosis may be prevented by the cell-seeded matrix.

“This biological approach is attractive because of its potential for aiding myocardial regeneration with a variety of cell types,” concluded Chachques.

“Cardiac stem cell repair is one of the most important new areas of research today,” says Cell Transplantation editor Paul Sanberg, PhD, DSc. “This special issue illustrates important new findings and the significant efforts being taken to develop these therapies and move them from the scientist’s bench to the bedside where in clinical practice they can make a difference in the lives of patients.”


 

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