Autologous cardiac progenitor cells (CPCs) isolated as cardiospheres (CSps) 
represent a promising candidate for cardiac regenerative therapy. A better 
understanding of the origin and mechanisms underlying human CSps formation and 
maturation is undoubtedly required to enhance their cardiomyogenic potential. 
Epithelial-to-mesenchymal transition (EMT) is a key morphogenetic process that 
is implicated in the acquisition of stem cell-like properties in different adult 
tissues, and it is activated in the epicardium after ischemic injury to the 
heart. We investigated whether EMT is involved in the formation and 
differentiation of human CSps, revealing that an up-regulation of the expression 
of EMT-related genes accompanies CSps formation that is relative to primary 
explant-derived cells and CSp-derived cells grown in a monolayer. EMT and CSps 
formation is enhanced in the presence of transforming growth factor β1 (TGFβ1) 
and drastically blocked by the type I TGFβ-receptor inhibitor SB431452, 
indicating that TGFβ-dependent EMT is essential for the formation of these 
niche-like 3D-multicellular clusters. Since TGFβ is activated in the myocardium 
in response to injury, our data suggest that CSps formation mimics an adaptive 
mechanism that could potentially be enhanced to increase in vivo or ex vivo 
regenerative potential of adult CPCs.