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Streptozotocin-induced partial beta cell depletion in nude mice without hyperglycaemia induces pancreatic morphogenesis in transplanted embryonic stem cells.

Takeshita F, Kodama M, Yamamoto H, Ikarashi Y, Ueda S, Teratani T, Yamamoto Y, Tamatani T, Kanegasaki S, Ochiya T, Quinn G

Section for Studies on Metastasis, National Cancer Center Research Institute, 1-1 Tsukiji, 5-chome, Chuo-ku, Tokyo, 104-0045, Japan.

AIMS/HYPOTHESIS: It appears that the adult pancreas has limited regenerative ability following beta cell destruction by streptozotocin (STZ). However, it is not clear if this limitation is due to an inability to respond to, rather than an absence of, regenerative stimuli. In this study we aimed to uncouple the regenerative signal from the regenerative response by using an exogenous stem cell source to detect regenerative stimuli produced by the STZ-injured pancreas at physiological blood glucose levels. METHOD: Adult nude mice received 150 mg/kg STZ and 1x10(6) J1 mouse embryonic stem (ES) cells by i.p. injection. Permanent beta cell depletion of 50% was estimated from the ratio of beta:alpha cells in pancreata from STZ-treated mice compared with control animals after 24 days. RESULTS: Transplanted ES cells homed to the STZ-injured pancreas and formed tumours. Immunocytochemical analysis of pancreas-associated ES tumours revealed foci containing insulin/PDX-1 double-positive and glucagon-positive/PDX-1-negative cell clusters associated with PDX-1-positive columnar lumenal epithelium and extensive alpha-amylase-positive pancreatic acini comprising approximately 0.1% of ES tumour volume. CONCLUSIONS/INTERPRETATION: These data indicate that (1) the adult pancreas produces a milieu of regenerative stimuli following beta cell destruction, and (2) this is not dependent on hyperglycaemic conditions; (3) these regenerative stimuli appear to recapitulate the signalling pathways of embryonic development, since both exocrine and endocrine lineages are produced from PDX-1-positive precursor epithelium. This model will be useful for characterising the regenerative mechanisms in the adult pancreas.

Published 10 November 2006 in Diabetologia, 49(12): 2948-58.
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