Autophagic cell death of pancreatic acinar cells in serine protease inhibitor Kazal type 3-deficient mice
Autophagic cell death of pancreatic acinar cells in serine protease inhibitor Kazal type 3-deficient mice
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DOI：
10.1053/j.gastro.2005.05.057
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发表时间：
2005-08-01
期刊：
影响因子：
29.4
通讯作者：
Yamamura, K
中科院分区：
文献类型：
--
作者：
Ohmuraya, M;Hirota, M;Yamamura, K
背景和目标：丝氨酸蛋白酶抑制剂Kazal 1型（SPINK 1），其结构类似于表皮生长因子，被认为可以抑制胰蛋白酶活性并预防胰腺炎。SPINK1基因的点突变似乎使人类易患胰腺炎;然而，SPINK1突变的临床意义仍然存在争议。本研究旨在阐明SPINK1的作用。方法：我们通过小鼠胚胎干细胞基因打靶产生Spink 3缺陷（Spink 3（-/-））小鼠。胚胎和新生儿胰腺进行了形态学和分子生物学分析。使用特异性探针显示腺泡细胞死亡期间发生的典型自噬。结果：Spink3（-/-）小鼠在交配后15.5天胰腺发育正常。然而，自噬变性的腺泡细胞，而不是导管或胰岛细胞，开始从16.5天后性交。出生后几天内胰腺和十二指肠细胞迅速死亡，并在出生后14.5天死亡。有有限的炎性细胞浸润，没有细胞凋亡的迹象。出生后7.5天，肾小管复合体中残留的导管样细胞强烈表达胰腺十二指肠同源结构域蛋白：1，胰腺干细胞的标志物，没有任何腺泡细胞再生的迹象。结论：Spink3（-/-）小鼠腺泡细胞的进行性消失是由于自噬性细胞死亡和再生障碍所致。因此，Spink3在维持腺泡细胞的完整性和再生中具有重要作用。
Background & Aims: Serine protease inhibitor Kazal type 1 (SPINK1), which is structurally similar to epidermal growth factor, is thought to inhibit trypsin activity and to prevent pancreatitis. Point mutations in the SPINK1 gene seem to predispose humans to pancreatitis; however, the clinical significance of SPINK1 mutations remains controversial. This study aimed to elucidate the role of SPINK1. Methods: We generated Spink3-deficient (Spink3(-/-)) mice by gene targeting in mouse embryonic stem cells. Embryonic and neonatal pancreases were analyzed morphologically and molecularly. Specific probes were used to show the typical autophagy that occurs during acinar cell death. Results: In Spink3(-/-) mice, the pancreas developed normally up to 15.5 days after coitus. However, autophagic degeneration of acinar cells, but not ductal or islet cells, started from day 16.5 after coitus. Rapid onset of cell death occurred in the pancreas and duodenum within a few days after birth and resulted in death by 14.5 days after birth. There was limited inflammatory cell infiltration and no sign of apoptosis. At 7.5 days after birth, residual ductlike cells in the tubular complexes strongly expressed pancreatic duodenal homeodomain-containing protein :1, a marker of pancreatic stem cells, without any sign of acinar cell regeneration. Conclusions: The progressive disappearance of acinar cells in Spink3(-/-) mice was due to autophagic cell death and impaired regeneration. Thus, Spink3 has essential roles in the maintenance of integrity and regeneration of acinar cells.