Cellular Cardiomyoplasty

Cellular cardiomyoplasty, the process by which injured myocardium is repaired by cell transplantation, has significant clinical potential (57,58). Much of the excitement about cell-based therapy lies in the premise that repairing the injured heart will overcome the inherent limitations for the broad application of both organ transplantation and mechanical assist devices. A thorough review of the literature for stem cell-mediated cardiac therapy is provided in Chapter 31, and thus the topic is only reviewed briefly in this section.

9.1. The Ideal Cell Population for Cardiomyoplasty

Although recent advances in the field of cardiomyoplasty have been achieved with the advent of stem cell technology, the "ideal" population of cells that is able to engraft damaged myocardium and restore cardiac function effectively without improper differentiation to other contaminating cell types is still an issue of debate. Many cell types with the potential to repair the injured heart have been considered, including differentiated cells (fetal myocytes or satellite muscle cells) and undifferentiated cells (embryonic or adult stem cells).

Although pluripotent embryonic stem cells offer the promise of functional plasticity and the ability to differentiate into any cell type in vitro, extensive experimentation in vivo is still necessary to direct the formation of integrated, functional cardiac tissue properly at the site of injury without improper differentiation to form teratomas or other noncardiac cell types. Multipotent tissue-specific cells that have already committed to a distinct lineage, such as hematopoietic stem cells, mesenchy-mal stem cells, and endothelial progenitor cells, have also pro

Pro Stem Cell Research

duced encouraging results (59). However, to date, the use of these cells often results in incomplete engraftment and a failure to restore cardiac function over time (60). Regardless of the cell type used in cardiomyoplasty, it is clear that animal models will again play a crucial role in the translational research that will be necessary to advance this theory out of the lab and into clinical practice.

9.2. Animal Models for Stem Cell Research

Although multiple animal species have been used for the study of cellular cardiomyoplasty, most investigators have chosen acute ischemia as their experimental model of choice. However, although effective treatment options for acute ischemia do exist, only limited options are available for chronic myocardial ischemia. This observation strongly suggests that further development of the chronic ischemia models using cardiomyoplasty is warranted. As with most research, the experimental hypothesis will remain fundamental in choosing the correct animal model. However, the availability of appropriate stem cell lines in the desired species will add additional limitations. Fully characterizing cell lines is important and advantageous so that functional changes of the therapy are correctly attributed to the appropriate precursor cell.

The multiple types of stem cells available for the rodent, specifically the rat and mouse, have made small animal models effective for investigations of stem cell engraftments. How ever, the differences in myocardial perfusion and ventricular thickness may confer differences in nutrient supplies that would support engraftment in small animal models, but may not be translatable to humans.

Ultimately, large animal models that better approximate the diseased human heart will be required to assess fully stem cell engraftment, differentiation, or functional improvement. Large animal models generally are considered better suited for assessment of myocardial function via angiography, echo-cardiography, or MRI; however, the limited availability of appropriate stem cell lines for use in these models has prevented the widespread use of large animal models.

Nevertheless, stem cell lines are currently under development for the pig, dog, and monkey at the University of Minnesota. More specifically, one laboratory has developed a canine model of cardiomyoplasty for chronic ischemia in which bone marrow-derived stem cells are used (Fig. 14). We have demonstrated successful engraftment (8%) and statistically significant sustained long-term improvement in regional myocardial function by MRI follow-up. Although successful, this first effort has resulted in more questions: How should we deliver cells? When should we deliver the cells? How many cells should be delivered? How often should we deliver cells? Much work has yet to be completed before it can be certain that stem cell therapies can be considered a viable treatment for various forms of myocardial disease.

9.3. Stem Cell Delivery Methods

Multiple methods of stem cell delivery have been investigated, including direct myocardial injection, peripheral transfusion, and stem cell mobilization (61). Direct epicardial myocardial injection can be fairly consistently completed intra-operatively during procedures such as coronary arterial bypass or valve operations. Endocardial injection will likely be completed using commercially available radiographic guided stem cell injection catheters (Fig. 15). Both transfusion and mobilization of resident stem cells offer the least invasive means of stem cell delivery. However, this requires the availability of effective homing signals to direct the correct location for engraftment. This last hurdle could possibly be overcome using guided direct myocardial injections, either surgically or via interventional catheter techniques.

Currently, we believe that multiple stem cell injections may be required to achieve full myocardial regeneration for therapeutic repair. As a result, the use of stem cell injection catheters may become the standard of practice. In addition, advanced imaging techniques such as MRI may allow localization of injured myocardium and direct, in real time, the stem cell injection catheters in the damaged area.

9.4. Stem Cell Engraftment Issues

The ability to track the implanted cell is critical not only to assess the potential of engraftment, but also later to determine differentiation and incorporation into the native tissue. Multiple techniques of cell labeling are currently under investigation, including the use of viral gene transduction (e.g., 4',6-diamidino-2-phenylindole [DAPI], green fluorescent gene, Lac Z), incorporation of dyes, and the use of metallic microparticles (62,63).

For example, gene insertion can be fairly easily accomplished (i.e., allowing for fluorescence microscopy or Q-PCR identification of the stem cell). However, the exact insertion site into the deoxyribonucleic acid (DNA) of the cell cannot currently be well controlled, introducing the possibility for nonexpression of the gene or potential disruption of normal cellular transcription and translation processes. The use of dyes incorporated into the cells by pinocytosis has been reported. The primary disadvantage of this technique has been the potential for dye incorporation into native cells in vivo. The use of metallic microparticles has received attention in that such particles may allow real-time identification of cells by MRI imaging and later pathologically by staining. However, information about the potential disruption of cellular function and possible uptake in vivo by native cells has yet to be elucidated fully.

9.5. Functional Assessment of Stem Cell Therapies

Many efforts to demonstrate improvement in cardiac function following cellular cardiomyoplasty have been undertaken. Methods include pressure measurements, ultrasonic microc-rystal placement, echocardiography, and MRI. Regardless of the specific method used by the investigators, minimal significant long-term follow-up studies currently exist in the literature. Thus, we conclude that much more research is required before this theory should be applied to humans.

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Fig. 15. Catheter-guided stem cell therapy for myocardial infarction. With permission from Katarzyna Simura.

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