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Surgery. 2004 Aug;136(2):449-57.

Hepatic regeneration and enforced PDX-1 expression accelerate transdifferentiation in liver.

Author information

1
Department of Surgery and Surgical Basic Science, Kyoto University, Kyoto, Japan.

Abstract

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.

PMID:
15300214
DOI:
10.1016/j.surg.2004.05.024
[Indexed for MEDLINE]

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