Hepatic regeneration and enforced PDX-1 expression accelerate transdifferentiation in liver
Hepatic regeneration and enforced PDX-1 expression accelerate transdifferentiation in liver
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DOI：
10.1016/j.surg.2004.05.024
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发表时间：
2004-08-01
期刊：
影响因子：
3.8
通讯作者：
Imamura, M
中科院分区：
文献类型：
--
作者：
Koizumi, M;Doi, R;Imamura, M
背景。胰腺十二指肠同源盒基因 1 (PDX-1) 作为成人胰腺器官发生和 β 细胞功能维持的关键调节因子具有双重作用。最近的研究表明肝脏和胰腺之间存在密切的谱系关系。在这项研究中，我们通过链脲佐菌素（STZ）处理的小鼠在肝再生条件下强制表达PDX-1来分析肝脏的可塑性。方法。通过粘粒-腺病毒DNA末端蛋白复合物方法构建复制缺陷型腺病毒。用 STZ (200 mg/kg ip) 治疗小鼠，并在第 0 天进行 40% 部分肝切除术。 24 小时后，通过尾部将 Ad-pdx-1 或 Ad-lacZ 2.0 x 10(9) PFU/体注射到未治疗（对照）、STZ 治疗或 STZ 加部分肝切除术 (Hx) 治疗的 ICR 小鼠中。 7天和14天后，通过免疫组织学和逆转录聚合酶链反应分析检查PDX-1和胰岛激素的表达。每 2 天测量一次血糖浓度。通过 ELISA 测定血清和肝脏提取物的免疫反应性胰岛素 (IRI)。结果。免疫组织化学显示，Ad-pdx-1 感染小鼠的大多数肝细胞 PDX-1 表达呈阳性。在未经治疗的小鼠中，很少有细胞表达胰岛素和其他激素。相比之下，STZ 治疗的小鼠中表达胰岛素和生长抑素，STZ 加 Hx 治疗的小鼠中表达更多的细胞。此外，还观察到其他 β 细胞标记物，如 GLUT2 和葡萄糖激酶。 STZ 治疗的小鼠和 STZ 加 Hx 治疗的小鼠的高血糖得到改善。 STZ 处理的小鼠和 STZ 加 Hx 处理的小鼠的血清和肝脏提取物的 IRI 增加。 STZ加Hx治疗的小鼠肝脏胰岛素阳性面积大于未治疗和STZ治疗的小鼠。结论。仅异位 PDX-1 表达可能不足以诱导肝脏中产生胰岛素的细胞。 STZ 诱导的高血糖加上导致糖尿病状态和肝再生的部分肝切除术可能会刺激肝细胞转分化为产生胰岛素的细胞。
Background. Pancreatic duodenal homeobox gene-1 (PDX-1) has a dual task as a key regulator in Pancreatic organogenesis and in functional maintenance of beta cells in adults. Recent studies have shown a close lineage relationship between the liver and the pancreas. In this study, we analyzed the plasticity of the liver by enforced expression of PDX-1 in streptozotocin (STZ)-treated mice under the condition of hepatic regeneration.Methods. Replication-deficient adenoviruses were constructed by the cosmid-adenoviral DNA terminal protein complex method. Mice were treated with STZ (200 mg/kg ip), and a 40% partial hepatectomy was performed at day 0. After 24 hours, Ad-pdx-1 or Ad-lacZ 2.0 x 10(9) PFU/body was injected via the tail vain into nontreated (control), STZ-treated, or STZ plus partial hepatectomy (Hx)-treated ICR mice. After 7 and 14 days, expression of PDX-1 and islet hormones was examined by immunohistologic and reverse transcription-polymerase chain reaction analysis. Blood glucose concentrations were measured every 2 days. Immunoreactive insulin (IRI) of serum and liver extract was measured by ELISA.Results. Most hepatocytes of Ad-pdx-1-infected mice were positive for PDX-1 expression by immunohistochemistry. In nontreated mice, very few cells expressed insulin and other hormones. In contrast, insulin and somatostatin were expressed in STZ-treated mice, and more cells were expressed in STZ plus Hx-treated mice. In addition, other beta-cell markers like GLUT2 and glucokinase were observed. Hyperglycemia was improved in STZ-treated mice and STZ plus Hx-treated mice. IRI of serum and liver extract was increased in STZ-treated mice and STZ plus Hx-treated mice. The insulin positive area of the liver in STZ plus Hx-treated mice was larger than that in nontreated and STZ-treated mice.Conclusions. Ectopic PDX-1 expression alone may be insufficient to induce insulin-producing cells in the liver. STZ-induced hyperglycemia plus partial hepatectomy that leads to diabetic state and hepatic regeneration may stimulate the transdifferentiation of liver cells into insulin-producing cells.