The quest to regenerate functional myocardium from stem cells following myocardial infarction has garnered a great deal of media attention and has become something of a holy grail in cardiovascular medicine. Despite the basic science of stem cells still being at an early stage, the first human trials have already been conducted – but the results thus far have been neutral at best with little or no evidence of clinical benefit. A significant bottleneck is the identification of a viable source of stem/progenitor cells that could contribute new muscle with the therapeutic ideal being to stimulate a resident source, thus avoiding the caveats of limited graft survival, restricted homing to the site of injury and host immune rejection.
In contrast to the bone marrow derived cells that have been generally used thus far the authors of this study, done in various experimental mouse models, demonstrate that the adult heart contains a resident stem or progenitor cell population, which has the potential to contribute bona fide terminally differentiated cardiomyocytes after myocardial infarction. By priming these cells with a peptide called thymosin β4 they were able to induce embryonic reprogramming resulting in the mobilization of this population and subsequent differentiation to give rise to de novo cardiomyocytes. Following experimentally induced myocardial infarction, these cells were shown to migrate to the site of injury and then differentiate without any evidence of cellular fusion into structurally and functionally active cardiomyocytes that showed evidence of gap junction formation with adjacent cells, synchronous calcium transients and the formation of operational contractile apparatus. Despite a low overall fraction of these cells being present at the site of injury and a relatively poor overall efficiency of differentiation, serial MRI scans revealed significant improvements in ejection fraction, cardiac volumes and scar size in comparison to sham treated animals. Unfortunately, only pre-treatment with thymosin β4 demonstrated these effects and further work will be needed translate these findings into potential therapies.
Conclusions
The peptide thymosin β4 is able to induce a resident population of cardiac progenitor cells to trans-differentiate into functioning cardiomyocytes following myocardial infarction leading to improvements in cardiac function. Future work may uncover viable cardiac regenerative therapies for use in clinical practice.
- Smart N, Bollini S, Dubé KN, Vieira JM, Zhou B, Davidson S, Yellon D, Riegler J, Price AN, Lythgoe MF, Pu WT, Riley PR. De novo cardiomyocytes from within the activated adult heart after injury. Nature. 2011 Jun 8. doi: 10.1038/nature10188. [Epub ahead of print]