TY - JOUR
T1 - Streptozotocin-induced diabetes can be reversed by hepatic oval cell activation through hepatic transdifferentiation and pancreatic islet regeneration
AU - Kim, Seungbum
AU - Shin, Jun Seop
AU - Kim, Hyun Jung
AU - Fisher, Robert C.
AU - Lee, Mi Ji
AU - Kim, Chan Wha
N1 - Funding Information:
This study was supported by a grant from Korea Food and Drug Administration (03092-073). SK and M-JL held Brain Korea 21 fellowships from Korea Ministry of Education and Human Resources Development.
PY - 2007/7/5
Y1 - 2007/7/5
N2 - Hepatic oval cells have shown the potential to transdifferentiate into insulin-producing cells when cultured with high glucose concentrations. However, it remains unknown whether the oval cells can contribute to insulin production in diabetic mice. In this study, our aim was to investigate the response of activated hepatic oval cells to hyperglycemic conditions. C57BL/6 mice were fed a diet containing 0.1% 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) for 4 weeks to activate the hepatic oval cell population before inducing hyperglycemia with streptozotocin (STZ). Despite the initial hyperglycemia (341±15 mg/dl), the blood glucose levels of DDC-STZ-treated mice were significantly improved within 6 weeks (185±12 mg/dl). During the initial hyperglycemic stage, DDC-STZ-treated livers expressed pancreatic developmental, endocrine and exocrine genes. Hepatic insulin production was confirmed by immunohistochemistry and ELISA. These results suggested that transdifferentiated hepatic oval cell population contributed to the amelioration of hyperglycemia. We additionally determined that DDC-STZ-treated pancreata played a critical role in complete reversal of hyperglycemia as evidenced by extensive β-cell regeneration and increase of pancreatic insulin content after STZ treatment, which is rarely observed in other adult STZ models. Reversal of hyperglycemia in this model seems to be accomplished by biphasic insulin augmentation, first by hepatic transdifferentiation, and followed by endogenous β-cell regeneration in the pancreas. The DDC-STZ treatment provides a novel injury model for better understanding of the functional behavior of hepatic and pancreatic stem/progenitor cell population under hyperglycemic condition, which may yield critical information for developing β-cell-based therapies to treat diabetes.
AB - Hepatic oval cells have shown the potential to transdifferentiate into insulin-producing cells when cultured with high glucose concentrations. However, it remains unknown whether the oval cells can contribute to insulin production in diabetic mice. In this study, our aim was to investigate the response of activated hepatic oval cells to hyperglycemic conditions. C57BL/6 mice were fed a diet containing 0.1% 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) for 4 weeks to activate the hepatic oval cell population before inducing hyperglycemia with streptozotocin (STZ). Despite the initial hyperglycemia (341±15 mg/dl), the blood glucose levels of DDC-STZ-treated mice were significantly improved within 6 weeks (185±12 mg/dl). During the initial hyperglycemic stage, DDC-STZ-treated livers expressed pancreatic developmental, endocrine and exocrine genes. Hepatic insulin production was confirmed by immunohistochemistry and ELISA. These results suggested that transdifferentiated hepatic oval cell population contributed to the amelioration of hyperglycemia. We additionally determined that DDC-STZ-treated pancreata played a critical role in complete reversal of hyperglycemia as evidenced by extensive β-cell regeneration and increase of pancreatic insulin content after STZ treatment, which is rarely observed in other adult STZ models. Reversal of hyperglycemia in this model seems to be accomplished by biphasic insulin augmentation, first by hepatic transdifferentiation, and followed by endogenous β-cell regeneration in the pancreas. The DDC-STZ treatment provides a novel injury model for better understanding of the functional behavior of hepatic and pancreatic stem/progenitor cell population under hyperglycemic condition, which may yield critical information for developing β-cell-based therapies to treat diabetes.
KW - Diabetes
KW - Hepatic oval cell
KW - Islet neogenesis
KW - Pancreas regeneration
KW - Stem cell
KW - Transdifferentiation
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U2 - 10.1038/labinvest.3700561
DO - 10.1038/labinvest.3700561
M3 - Article
C2 - 17483848
AN - SCOPUS:34250349195
VL - 87
SP - 702
EP - 712
JO - Laboratory Investigation
JF - Laboratory Investigation
SN - 0023-6837
IS - 7
ER -