Primitive cells and tissue regeneration.

In the last few years, several experimental studies have used stem cells of different sources to reconstitute damaged tissues.1 The brain and the heart have been the most investigated organs because of the long-standing view of the lack of regenerating potential of neurons and myocytes.2,3 Bone marrow stem cells (BMSCs) have been reported capable of transdifferentiating in various cell lineages distinct from the site of origin4 and, because of this property, they may constitute a new form of cellular therapy. Neuronal and myocardial growth mediated by bone marrow cells (BMCs) has been demonstrated, but these results have been challenged5,6 and the issue of BMSC transdifferentiation has become highly controversial. Heated debates at scientific meetings, letters in high-profile journals, and reports with contradicting observations have raised questions on the plasticity of BMSCs.5–7 If negative results would be more cautiously interpreted instead of being blown out of context, it is likely that the actual role that adult stem cells play in the repair of tissues and organs would be better understood and appreciated. This is particularly relevant when negative data are dropped as “valid” statements from the podium and are quoted before they undergo peer review and publication.6 A good example of the opposite approach is found in the study of Chen and colleagues8 in this issue of Circulation Research. The authors have utilized, among other sophisticated techniques, confocal microscopy to identify and characterize an important new function of human pluripotent adult mesenchymal BMSCs. In this report, an unequivocal demonstration was obtained on the ability of these cells to deliver vascular endothelial growth factor (VEGF) to an ischemic region of the brain. VEGF accumulation coupled with endogenous activation of endothelial cells and VEGF synthesis promoted vessel formation after stroke. BMSCs via VEGF secretion acted as a chemoattractant for circulating and resident endothelial progenitor cells. Homing of these early committed cells led to the reconstitution of a vascular network within the damaged portion of the brain.8 Similarly, BMCs stimulated the growth of the coronary vasculature and microvasculature, and the regeneration of cardiomyocytes improving the performance of the postinfarcted heart.9,10 It is noteworthy that administration of VEGF by different modalities in various aspects of ischemic heart disease enhances coronary blood flow and cardiac hemodynamics,11 mimicking the effects of human mesenchymal BMSCs on the infarcted brain.8 The broad developmental potential of BMCs has recently been confirmed and extremely well documented in the brain,12,13 skeletal muscle,14 retina, and intestinal epithelium.15 However, the identity of the cells involved has not been clearly elucidated. The quandary of transdifferentiation of adult primitive cells into cell lineages different from those of the tissue of origin remains to be completely resolved, although accumulating evidence favors this possibility.16