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Department of Cardiovascular Surgery, University Medical Center, Hugstetter Str. 55, 79106 Freiburg, Germany
Received 24 March 2008; received in revised form 24 March 2008; accepted 25 March 2008.
* Corresponding author. Tel.: +49 761 270 7220; fax: +49 761 270 7220. (Email: claudia.heilmann{at}uniklinik-freiburg.de).
The comprehensive stem cell research of the last two decades has fertilized the hope for myocardial regeneration. Research in the cardiac field has been spurred by the observations that, in contradiction to former predications, there is a proliferation of cardiomyocytes in the full-grown heart and that there are indeed cardiac progenitor cells inside the myocardium and in the peripheral blood even in the adult. Myocardial proliferation and differentiation of progenitor cells occur on demand and depend on a favorable milieu.
Attempts with direct injection of stem cells into the damaged myocardium have been limited by the low number of surviving cells. In parallel, the importance of paracrine effects of stem cells and other cell types which invade the treated area has been recognized [1]. These properties include stimulation of vasculogenesis and angiogenesis, but also direct anti-apoptotic effects on cardiomyocytes. In consequence, scaffold-based approaches have been developed. This idea also sheds a new light on the older concept of cardiomyoplasty. Scaffolds of biological and of artificial origin have both been used. They are employed as carriers for, or seeded with, stem cells. Migration of the stem cells into the damaged myocardium and subsequent differentiation to cardiomyocytes is hoped for in addition to the assumed paracrine effects. However, there is only very scarce evidence so far that cardiomyocyte differentiation can be induced in vivo by any approach. Beyond differentiation, electromechanical coupling of new cardiomyocytes remains the ultimate requirement for true cardiac regeneration.
In this issue, Derval and co-workers [2] present a study on restoration of infarcted myocardium. They employ a mouse model of cryogenic infarction. After 30 days, a muscle pouch is applied which is filled with isolated GFP-labelled mesenchymal stem cells or endothelial progenitor cells. In some experiments, these cell types are mixed with unlabelled bone marrow cells to supply them with the necessary growth factors and cytokines. The authors aim at vascular and cardiac regeneration of the infarcted myocardium. The labelled mesenchymal stem cells are observed to invade the scar, whereas the endothelial progenitor cells do not. The bone marrow cells are not followed up. As a result, the authors find an increased thickness of the scar but no evidence of myocardial or vascular regeneration from progenitor cells. However, a hemodynamic improvement is noted.
Mesenchymal stem cells have been isolated from various sources, including bone marrow, and have been shown to contain the potential of differentiation to cardiomyocytes. The results of the study indicate, however, that a scar does not present the appropriate environment for this direction of differentiation. It seems likely that the isolated and the bone marrow-derived mesenchymal stem cells differentiate to fibroblasts. This would sufficiently explain the observed proliferative activities within the scar and its thickening. Nevertheless, the study is not to be considered futile beside its contribution to the methodical search for opportunities to regenerate infarcted myocardium. First, a stable and sufficiently thick scar could prevent the development of a life-threatening aneurysm. Second, attempts have been made to induce transdifferentiation of fibroblasts to cardiomyocyte-like cells with or without transitory dedifferentiation to pluripotent cells. These approaches have been successful in some aspects in vitro.
Moreover, every cell-based strategy of myocardial regeneration has improved the hemodynamic myocardial function so far [3]. The reasons for this phenomenon are not yet elucidated. Explanations include paracrine effects and induced revascularization. From the clinical point of view, efforts to achieve a ‘mere’ functional healing of the heart are even as justified as is the research on molecular pathways of stem cell-dependent cellular myocardial regeneration.
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