Degradation of type IV collagen by matrix metalloproteinases is an important step in the epithelial-mesenchymal transformation of the endocardial cushions

Morphogenesis of some tissues and organs in the developing embryo requires the transformation of epithelial cells into mesenchyme followed by cell mot ility and invasion of surrounding connective tissues. Details of the mechan isms involved in this important process are beginning to be elucidated. The epithelial-mesenchymal transformation (EMT) process involves many steps, o ne of which is the upregulation and activation of specific extracellular pr oteinases including members of the matrix metalloproteinase (MMP) family. H ere we analyze the role of MMPs in the initiation of the mesenchymal cell p henotype in the developing heart, and find that they are necessary for the invasion of mesenchymal cells into the extracellular matrix of the endocard ial cushion tissues. An important requirement in the formation of this mese nchyme is the turnover of type IV collagen along the basal surface of endoc ardial cells. In vitro experiments suggest that type IV collagen does not p rovide a suitable migratory substrate for endocardial cushion cells unless MMP-2 and MT-MMP are active. Relevant MMPs were found to be upregulated by factors known to be involved in the induction of the EMT such as TGF beta3. These results provide evidence of an important role for MMPs during a spec ific stage of the epithelial mesenchymal transformation in the embryonic he art, and suggest that specific cell-matrix interactions which facilitate ce ll migration only occur when the composition of the surrounding extracellul ar matrix is proteolytically altered. (C) 2000 Academic Press.