Hepatic regeneration and enforced PDX-1 expression accelerate transdifferentiation in liver.
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.
Department of Surgery and Surgical Basic Science, Kyoto University, Kyoto, Japan.
Masayuki
M
Koizumi
Ryuichiro
R
Doi
Eiji
E
Toyoda
Sidhartha S
SS
Tulachan
Kazuhiro
K
Kami
Tomohiko
T
Mori
Daisuke
D
Ito
Yoshiya
Y
Kawaguchi
Koji
K
Fujimoto
George K
GK
Gittes
Masayuki
M
Imamura
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D019556:COS Cells; D002454:Cell Differentiation; D051273:Glucose Transporter Type 2; D006498:Hepatectomy; D018398:Homeodomain Proteins; D006801:Humans; D007328:Insulin / Q000097:blood; D008099:Liver / Q000166:cytology*; D008115:Liver Regeneration; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009004:Monosaccharide Transport Proteins / Q000032:analysis; D013311:Streptozocin; D015534:Trans-Activators / Q000032:analysis / Q000502:physiology*
D001786:Blood Glucose; D051273:Glucose Transporter Type 2; D018398:Homeodomain Proteins; D007328:Insulin; D009004:Monosaccharide Transport Proteins; D015534:Trans-Activators; C084010:pancreatic and duodenal homeobox 1 protein; D013311:Streptozocin