Stem cells and cardiovascular repair: a role for natural and synthetic molecules harboring differentiating and paracrine logics

Stem cells hold considerable promise for cardiovascular rescue in patients with heart failure due to myocardial infarction or hereditary cardiomyopathies. However, cardiogenesis, one of the earliest and most complex morphogenetic events in the embryo, is only partially exploited at molecular level. The yield of myocardial cells spontaneously derived from human embryonic or adult stem cells is extremely low (usually less than 0.1%). Moreover, it is now evident that secretion of specific growth factors from transplanted stem cells may activate angiogenic, antiapoptotic and antifibrotic paracrine patterning within the recipient heart, playing a major role in tissue repair. Within this context, targeting stem cell fate at the level of gene expression represents a potentially powerful therapeutic approach to afford a high-throughput of cardiovascular lineage commitment and paracrine secretion of "trophic factors". Cell-based phenotypic- and pathway-specific screens of natural and synthetic compounds have provided a number of molecules achieving selective control of stem cell growth and differentiation. Novel hyaluronan mixed esters of butyric and retinoic acids have been recently synthesized, emerging as new tools for manipulation of cardio/vasculogenic gene expression through the modulation of targeted signaling pathways and chromatin-remodeling enzymes. These molecules have coaxed both murine embryonic and human mesenchymal stem cells towards cardiovascular decision and paracrine secretion of bioactive factors, remarkably enhancing the rescuing potential of human stem cells in in vivo animal models of myocardial infarction. These molecules may ultimately provide new insights in stem cell biology and pave the way to novel approaches in tissue engineering and cardiovascular repair.