Streptozotocin-induced diabetes can be reversed by hepatic oval cell activation through hepatic transdifferentiation and pancreatic islet regeneration

Abstract

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 (341715 mg/dl), the blood glucose levels of DDC-STZ-treated mice were significantly improved within 6 weeks (185712 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 b-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 b-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 b-cell-based therapies to treat diabetes. The pancreatic endocrine compartment is composed of the islets of Langerhans, which are clusters of four cell types that synthesize insulin (b-cells), glucagon (a-cells), somatostatin (d-cells) and pancreatic polypeptide (pp-cells). In mature rodent pancreatic islets, b-cells are located in the core, whereas a-, d-and pp-cells are in the rim. The pancreatic bcell possesses the ability to respond to minor increases in the plasma glucose levels, thereby keeping the blood glucose level within a very narrow range. 1 Progressive destruction of pancreatic b-cell leading to decreased insulin production and subsequent hyperglycemia is observed in all forms of diabetes mellitus. Therefore, the number of functional b-cells in the pancreas is of decisive importance in the development and progress of the disease. To date, the most effective long-term treatment of diabetes is islet transplantation, a procedure known as the Edmonton protocol. 2 However, there is currently a severe shortage of pancreas donors, creating a need for new strategies to generate pancreatic b-cells either in vitro or in vivo. Pancreatic stem/progenitor cells should be considered as the primary sources to generate insulin-producing cells. However, to dat...

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Recent Progress on Tissue-Resident Adult Stem Cell Biology and Their Therapeutic Implications

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Camel’s wharton jelly mesenchymal stem cell is a novel tool for regeneration of induced diabetes mellitus

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