Stem cells and cardiac repair: a critical analysis.

Utilizing stem cells to repair the damaged heart has seen an intense amount of activity over the last 5 years or so. There are currently multiple clinical studies in progress to test the efficacy of various different cell therapy approaches for the repair of damaged myocardium that were only just beginning to be tested in preclinical animal studies a few years earlier. This rapid transition from preclinical to clinical testing is striking and is not typical of the customary timeframe for the progress of a therapy from bench-to-bedside. Doubtless, there will be many more trials to follow in the upcoming years. With the plethora of trials and cell alternatives, there has come not only great enthusiasm for the potential of the therapy, but also great confusion about what has been achieved. Cell therapy has the potential to do what no drug can: regenerate and replace damaged tissue with healthy tissue. Drugs may be effective at slowing the progression of heart failure, but none can stop or reverse the process. However, tissue repair is not a simple process, although the idea on its surface is quite simple. Understanding cells, the signals that they respond to, and the keys to appropriate survival and tissue formation are orders of magnitude more complicated than understanding the pathways targeted by most drugs. Drugs and their metabolites can be monitored, quantified, and their effects correlated to circulating levels in the body. Not so for most cell therapies. It is quite difficult to measure cell survival except through ex vivo techniques like histological analysis of the target organ. This makes the emphasis on preclinical research all the more important because it is only in the animal studies that research has the opportunity to readily harvest the target tissues and perform the detailed analyses of what has happened with the cells. This need for detailed and usually time-intensive research in animal studies stands in contrast to the rapidity with which therapies have progressed to the clinic. It is now becoming clear through a number of notable examples that progress to the clinic may have occurred too quickly, before adequate testing and independent verification of results could be completed (Check, Nature 446:485-486, 2007; Chien, J Clin Investig 116:1838-1840, 2006; Giles, Nature 442:344-347, 2006). Broad reproducibility and transfer of results from one lab to another has been and always will be essential for the successful application of any cell therapy. So, what is the prognosis for cell therapy to repair heart damage? Will there be an approved cell therapy, or multiple ones, or will it require combinations of more than one cell type to be successful? These are questions often asked. The answers are difficult to know and even more difficult to predict because there are so many variables associated with cell-based therapies. There is much about the biology of cell systems that we still do not understand. Much of the pluripotency or transdifferentiation phenomena (see below) being observed go against accepted and well-tested principles for cell development and fate choice, and has caused a reevaluation of long-accepted theories. Clearly, new pathways for tissue repair and regeneration have been uncovered, but will these new pathways be sufficient to effect significant tissue repair and regeneration? Despite the false starts so far, there is the strong likelihood one or possibly multiple cell therapies will succeed. Clearly, important information has been gained, which should better guide the field to achieving success. When there is the successful verification in patients of a cell therapy, there will be an explosion of technological advances around the approach(es) that succeed. Whatever cells get approved accompanying them will be: more effective delivery methods; growth and storage methods; combination therapies, mixes of cells or cells + gene therapies; combinations with biomaterials and technologies for immune protection, allowing allografting. There are many parallel paths of technology development waiting to be brought together once there is an effective cellular approach. The coming years will no doubt bring some exciting developments.