濱本 耕平

The mechanism that initiates regeneration of pancreatic beta-cells is not clear at present. The vagal nerve is implicated in the regulation of gastrointestinal functions, glucose metabolism and proliferation of pancreatic beta-cells under physiological conditions. To elucidate the triggering mechanism of the regeneration of pancreatic beta-cells, we examined the involvement of the vagal nerve. To this end, we employed a rat pancreatic duct ligation (DL) model, in which profound beta-cell neogenesis and beta-cell proliferation were observed within a week. We administered atropine to block the vagal nerve. Administration of atropine inhibited proliferation of beta-cells in both islets and islet-like cell clusters (ICC), without affecting ductal cell proliferation in the ligated pancreas. The numbers of PDX-1 and MafB-positive cells in or attaching to the ducts were significantly reduced by atropine. MafB/glucagon and MafB/insulin double-positive cells were also decreased by atropine. Finally, atropine reduced the number of MafA-positive ductal cells, all of which were positive for insulin, by 50% on day 5. These results strongly suggest that the vagal nerve is involved in beta-cell proliferation, induction of endocrine progenitors and neogenesis of alpha- and beta-cells.

Extracellular matrix (ECM) modulates differentiation of pancreatic beta-cells during development. However, the mechanism by which ECM proteins modulate differentiation is not totally clear. We investigated the effect of ECM proteins on differentiation beta-cells in vitro. We investigated the effect of basement membrane ECM on differentiation of AR42J cells and rat ductal cells. First, we examined the effect of reconstituted basement membrane, Matrigel on differentiation of AR42J cells induced by activin and betacellulin. Matrigel augmented insulin production and increased the expression of GLUT2, SUR1, and glucokinase. Among various transcription factors investigated, Matrigel markedly upregulated the expression of Pax6. When Pax6 was overexpressed in cells treated with activin and betacellulin, the expression of insulin was upregulated. Conversely, knockdown of Pax6 significantly reduced the insulin expression in cells cultured on Matrigel. The effects of Matrigel on insulin-production and induction of Pax6 were reproduced partially by laminin-1, a major component of Matrigel, and inhibited by anti-integrin-beta 1 antibody. Matrigel also enhanced the activation of p38 mitogen-activated kinase induced by activin and betacellulin, which was inhibited by anti-beta 1 antibody. Finally, the effect of Matrigel on differentiation was reproduced in rat cultured ductal cells, and Matrigel also increased the expression of Pax6. These results indicate that basement membrane ECM augments differentiation of pancreatic progenitor cells to insulin-secreting cells by upregulating the expression of Pax6. J. Cell. Biochem. 112: 318329, 2011. (C) 2010 Wiley-Liss, Inc.

Mesial temporal sclerosis is a common form of symptomatic, localization-related epilepsy in children and adolescents, but its occurrence with acute lymphoblastic leukemia is rare. We present clinical records and neuroimaging results of a 13-year-old patient with acute lymphoblastic leukemia who developed recurrent partial seizures after an episode of leukoencephalopathy thought to be caused by methotrexate. Neuroradiologic images revealed hippocampal abnormalities consistent with the findings of mesial temporal sclerosis. Mesial temporal sclerosis was not previously reported in acute lymphoblastic leukemia patients with methotrexate-induced leukoencephalopathy. However, our case suggests that the pathogenesis of mesial temporal sclerosis may be associated with methotrexate-induced neurotoxicity. © 2009 Elsevier Inc. All rights reserved.