PubMed · 82767
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1978-12-09. Dipyridamole and platelet function.. https://pubmed.ncbi.nlm.nih.gov/82767/
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We previously demonstrated that dexamethasone (Dex) induces the transdifferentiation (or conversion) of the pancreatic progenitor cell line AR42J-B13 (B13) to hepatocytes based on the expression of liver proteins. We have extended our original observations to determine: (1) the effects of Dex on pancreatic gene expression; (2) the time course of expression of liver enriched transcription factors during conversion from pancreatic to hepatic phenotype; (3) the functional potential of transdifferentiated hepatocytes; (4) the proliferative capacity of transdifferentiated hepatocytes; and (5) whether ectopic expression of transcription factors can induce the hepatic phenotype in pancreatic B13 cells. The results were as follows. The B13 cell markers amylase, synaptophysin, and neurofilament were lost in transdifferentiated hepatocytes compared to control cells and the liver enriched transcription factors C/EBPbeta and C/EBPalpha were induced first, followed by HNF4alpha and then RXRalpha. Using RT-PCR analysis and immunolocalisation studies, we detected hepatic markers (e.g., apolipoprotein B) in Dex-treated cells. In transdifferentiated hepatocytes albumin was secreted, insulin stimulated lipid deposition and ciprofibrate enhanced the expression of catalase. Proliferation of transdifferentiated hepatocytes is promoted in the presence of HGF and NEAA as indicated by the co-expression of the cell cycle markers cyclin D and phosphohistone H3 with liver proteins. Lastly, ectopic expression of C/EBPalpha or C/EBPbeta in AR42J-B13 cells was sufficient to induce transdifferentiation, based on nuclear localization of HNF4alpha and induction of UDP-glucuronosyltransferase expression. These results indicate that the B13 progenitor cell model is suitable for studying liver function and for understanding the molecular and cellular events that occur during transdifferentiation.
In earlier work, we reported on the manner with which lipophilic drug molecules interact with the cell membrane in order to (a) enter the bilayer and laterally diffuse to their respective protein sites of action, or (b) penetrate this biological barrier to reach the cell interior. A remaining uncertainty is how lipophilic molecules reach the hydrophobic membrane core after traversing the aqueous medium and membrane polar surface. Here we present preliminary data using deuterium NMR, demonstrating the role of bovine serum albumin in facilitating this process. Our observation allows us to postulate a mechanism by which the passive transport of lipophilic ligands across the membrane can be greatly enhanced through the assistance of carrier proteins.
BACKGROUND: Hepatocellular differentiation of pancreatic cells has been observed under certain conditions in several species, including humans. Their cell of origin and biology has remained controversial. Generally, these lesions have been considered a degenerative process. The present study describes a neoplastic hepatocellular lesion in Syrian hamsters. METHODS AND RESULTS: Syrian hamsters were treated with a high dose of pancreatic carcinogen, N-nitrosobis(2-oxopropyl)amine. The lesion was confined within a single islet and expressed albumin and HSA (hepatocyte-specific antigen). The pleomorphic tumor cells exhibited numerous mitotic figures and were intermingled with insulin and glucagon cells. The hamster had multicentric premalignant and malignant ductal-type lesions, most of which appeared to arise from within the islets. This is the first demonstration of pancreatic hepatoma. CONCLUSION: Pancreatic islet cells appear to have the potential to transdifferentiate into neoplastic hepatocytes.