TGF-BETA PLAYS A KEY ROLE IN MORPHOGENESIS OF THE PANCREATIC-ISLETS OF LANGERHANS BY CONTROLLING THE ACTIVITY OF THE MATRIX METALLOPROTEINASE MMP-2

Islets of Langerhans are microorgans scattered throughout the pancreas , and are responsible for synthesizing and secreting pancreatic hormon es. While progress has recently been made concerning cell differentiat ion of the islets of Langerhans, the mechanism controlling islet morph ogenesis is not known. It is thought that these islets are formed by m ature cell association, first differentiating in the primitive pancrea tic epithelium, then migrating in the extracellular matrix, and finall y associating into islets of Langerhans. This mechanism suggests that the extracellular matrix has to be degraded for proper islet morphogen esis. We demonstrated in the present study that during rat pancreatic development, matrix metalloproteinase 2 (MMP-2) is activated in vivo b etween E17 and E19 when islet morphogenesis occurs. We next demonstrat ed that when E12.5 pancreatic epithelia develop in vitro, MMP-2 is act ivated in an in vitro model that recapitulates endocrine pancreas deve lopment (Miralles, F., P. Czernichow, and R. Scharfmann. 1998. Develop ment. 125: 1017-1024). On the other hand, islet morphogenesis was impa ired when MMP-2 activity was inhibited. We next demonstrated that exog enous TGF-beta 1 positively controls both islet morphogenesis and MMP- 2 activity. Finally, we demonstrated that both islet morphogenesis and MMP-2 activation were abolished in the presence of a pan-specific TGF -P neutralizing antibody. Taken together, these observations demonstra te that in vitro, TGF-P is a key activator of pancreatic MMP-2, and th at MMP-2 activity is necessary for islet morphogenesis.