TGF-beta plays a key role in morphogenesis of the pancreatic islets of Langerhans by controlling the activity of the matrix metalloproteinase MMP-2.
TGF-beta plays a key role in morphogenesis of the pancreatic islets of Langerhans by controlling the activity of the matrix metalloproteinase MMP-2.
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DOI：
10.1083/jcb.143.3.827
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发表时间：
1998-11-02
影响因子：
7.8
通讯作者：
Scharfmann, R
中科院分区：
文献类型：
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作者：
Miralles, F;Battelino, T;Czernichow, P;Scharfmann, R
胰岛是分散在胰腺中的微器官，负责合成和分泌胰腺激素。虽然最近已经取得了进展，关于细胞分化的胰岛，控制胰岛形态发生的机制是未知的。据认为，这些胰岛是由成熟细胞联合形成的，首先在原始胰腺上皮中分化，然后在细胞外基质中迁移，最后联合成胰岛。这一机制表明，细胞外基质必须降解，以实现适当的胰岛形态发生。我们在本研究中证明，在大鼠胰腺发育过程中，当胰岛形态发生时，基质金属蛋白酶2（MMP-2）在E17和E19之间在体内被激活。我们接下来证明，当E12.5胰腺上皮细胞在体外发育时，MMP-2在体外模型中被激活，该体外模型再现了内分泌胰腺发育（Miralles，F.，P. Czernichow和R.沙夫曼1998.发展125：1017-1024）。另一方面，当MMP-2活性被抑制时，胰岛形态发生受损。我们接下来证明了外源性TGF-β1积极控制胰岛形态发生和MMP-2活性。最后，我们证明了在存在泛特异性TGF-β中和抗体的情况下，胰岛形态发生和MMP-2活化均被消除。总之，这些观察结果表明，在体外，TGF-β是胰腺MMP-2的关键激活剂，并且MMP-2活性是胰岛形态发生所必需的。
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 morphogenesis occurs. We next demonstrated that when E12.5 pancreatic epithelia develop in vitro, MMP-2 is activated in an in vitro model that recapitulates endocrine pancreas development (Miralles, F., P. Czernichow, and R. Scharfmann. 1998. Development. 125: 1017–1024). On the other hand, islet morphogenesis was impaired when MMP-2 activity was inhibited. We next demonstrated that exogenous TGF-β1 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-β neutralizing antibody. Taken together, these observations demonstrate that in vitro, TGF-β is a key activator of pancreatic MMP-2, and that MMP-2 activity is necessary for islet morphogenesis.