Multiple transforming growth factor-β isoforms and receptors function during epithelial-mesenchymal cell transformation in the embryonic heart

Epithelial-mesenchymal cell transformation (EMT) is a critical process during development of the heart valves. Transition of endothelial cells into mesenchymal cells in the atrioventricular (AV) canal and the outflow tract regions of the heart form the cardiac cushions that eventually form the heart valves. Collagen gel invasion assay has aided in the identification of molecules that regulate EMT. Among those, transforming growth factor-β (TGF-β) ligands and receptors demonstrate a critical role during EMT. In the chick, TGF-β ligands and some receptors have specific functions during EMT. TGF-β2 mediates endothelial cell-cell activation and separation, and TGF-β3 mediates cell invasion into the extracellular matrix. Receptors involved in the EMT process include TGF-β receptor type II (TBRII), TBRIII, endoglin and the TBRI receptors, ALK2 and ALK5. In contrast, in the mouse model, TGF-β2 is the only ligand involved in EMT. The TGF-β2 null mouse has either increased EMT or a mesenchymal cell proliferation after EMT. However, functional studies of TGF-β1 in vivo and in vitro showed that TGF-β1 functions in the EMT of the mouse AV canal. Latent TGF-β-binding protein (LTBP-1) and endoglin have a role in the EMT process. Therefore, TGF-βs mediate cardiac EMT in both embryonic species. Further studies will reveal the identification of ligand and receptor-specific activities.