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Department of Clinical Sciences, University ‘La Sapienza’, Rome, Italy
¹ National Centre for Food Quality and Risk Assessment, Section of Nutrition, Istituto Superiore di Sanità, Rome, Italy
² Division of Endocrinology and Metabolism, Cedars-Sinai Medical Center, University of California, Los Angeles, CA, USA
³ Department of Experimental Medicine and Pathology, University ‘La Sapienza’, Rome, Italy

(Requests for offprints should be addressed to E Anastasi; Email: emanuela.anastasi{at}uniroma1.it)

The elucidation of mechanisms regulating the regeneration and survival of pancreatic beta cells has fundamental implications in the cell therapy of type 1 diabetes. The present study had the following three aims: 1. to investigate whether pancreatic ductal epithelial cells can be induced to differentiate into insulin-producing cells by exposing them to hepatocyte growth factor (HGF); 2. to characterize some of the molecular events leading to their differentiation toward a beta-cell-like phenotype; 3. to evaluate the susceptibility of newly differentiated insulin-secreting cells to cytokine-induced apoptosis, a mechanism of beta-cell destruction occurring in type 1 diabetes. We demonstrated that HGF-treated rat pancreatic ductal cell line (ARIP) cells acquired the capability to transcribe the insulin gene and translate its counterpart protein. HGF-treated cells also exhibited a glucose-dependent capability to secrete insulin into the cultured medium. Expression analysis of some of the genes regulating pancreatic beta-cell differentiation revealed a time-dependent transcription of neurogenin-3 and Neuro-D in response to HGF. Finally, we determined the susceptibility to proinflammatory cytokine (PTh1)-induced apoptosis by incubating HGF-treated and untreated ARIP cells with a cocktail of interleukin-1 beta (IL-1ß), tumor necrosis factor-alpha (TNF-) and interferon-gamma (IFN-). Such treatment induced apoptotic death, as determined by the TUNEL technique, in about 40% of HGF-treated, insulin-secreting ARIP cells, while untreated ARIP cells were resistant to PTh1-induced apoptosis. In conclusion, we showed that HGF promotes the differentiation of ARIP cells into pancreatic beta-cell-like cells, and that the differentiation toward an insulin-secreting phenotype is associated with the appearance of susceptibility to cytokine-induced apoptosis.

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				C. Santangelo, P. Matarrese, R. Masella, M. C. Di Carlo, A. Di Lillo, B. Scazzocchio, E. Vecci, W. Malorni, R. Perfetti, and E. Anastasi Hepatocyte growth factor protects rat RINm5F cell line against free fatty acid-induced apoptosis by counteracting oxidative stress J. Mol. Endocrinol., January 1, 2007; 38(1): 147 - 158. [Abstract] [Full Text] [PDF]