Tgf-␤ 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 hormones. While progress has recently been made concerning cell differentiation of the islets of Langerhans, the mechanism controlling islet morphogenesis is not known. It is thought that these islets are formed by mature cell association , first differentiating in the primitive pancreatic epithelium, then migrating in the extracellular matrix, and finally associating into islets of Langerhans. This mechanism suggests that the extracellular matrix has to be degraded for proper islet morphogenesis. We demonstrated in the present study that during rat pancreatic development, matrix metalloproteinase 2 (MMP-2) is activated in vivo between E17 and E19 when islet mor-phogenesis occurs. We next demonstrated that when E12.5 pancreatic epithelia develop in vitro, MMP-2 is activated in an in vitro model that recapitulates endo-On the other hand, islet morphogenesis was impaired when MMP-2 activity was inhibited. We next demonstrated that exogenous TGF-␤ 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-␤ neutralizing antibody. Taken together, these observations demonstrate that in vitro, TGF-␤ is a key activator of pancreatic MMP-2, and that MMP-2 activity is necessary for islet morphogenesis. I n the adult rat, the endocrine pancreatic tissue represents 2% of the pancreatic mass. This endocrine tissue is composed of cells associated into spherical microor-gans: the islets of Langerhans. These islets (around 5,000 per pancreas) contain a few thousand cells that express insulin (beta cells), glucagon, somatostatin, or pancreatic polypeptides. Beta cells are localized in the center of the islets, while the other endocrine cells are localized in the periphery. During development, it is thought that precursor cells that will give rise to pancreatic endocrine cells are present in the primitive pancreatic duct epithelium where they differentiate into endocrine cells (30). Once differentiated, these cells will migrate into the interstitial matrix, and finally aggregate to form the islets of Langerhans (9). While progress has recently been made concerning the early steps of endocrine cell differentiation (1, 19, 40, 43), the mechanism leading to islet morphogenesis remains poorly understood. The focus of the present work is islet morpho-genesis. Cell migration of pancreatic endocrine cells through the extracellular matrix (ECM) 1 is thought to constitute an essential step in islet morphogenesis (8, 9). In the pancreas as in other organs, the …

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