Islet duodenal homeobox 1 (IDX-1/PF-1/STF-1/PDX-1), a homeodomain protein that transactivates the insulin promoter, has been shown by targeted gene ablation to be required for pancreatic development. After 90% pancreatectomy (Px), the adult pancreas regenerates in a process recapitulating embryonic development, starting with a burst of proliferation in the epithelium of the common pancreatic duct. In this model, IDX-1 mRNA was detected by semiquantitative reverse transcription-polymerase chain reaction in total RNA from isolated common pancreatic ducts at levels 10% of those of isolated islets. The IDX-1 mRNA levels were not significantly different for common pancreatic ducts of Px, sham Px, and unoperated rats and did not change with time after surgery. By immunoblot analysis, IDX-1 protein was only faintly detected in these ducts 1 and 7 days after Px or sham Px but was easily detected at 2 and 3 days after Px. Similarly, IDX-1 immunostaining was barely detectable in sham or unoperated ducts but was strong in ducts at 2-3 days after Px. The increase of IDX-1 immunostaining followed that of BrdU incorporation (proliferation). These results indicate a posttranscriptional regulation of the IDX-1 expression in ducts. In addition, islets isolated 3-7 d after Px showed higher IDX-1 protein expression than control islets. Thus, in pancreatic regeneration IDX-1 is upregulated in newly divided ductal cells as well as in islets. The timing of enhanced expression of IDX-1 implies that IDX-1 is not important in the initiation of regeneration but may be involved in the differentiation of ductal cells to beta-cells.

With the increasing success of islet transplantation, beta-cell replacement therapy has had renewed interest. To make such a therapy available to more than a few of the thousands of patients with diabetes, new sources of insulin-producing cells must become readily available. The most promising sources are stem cells, whether embryonic or adult stem cells. Clearly identifiable adult pancreatic stem cells have yet to be characterized. Although considerable evidence suggests their possibility, recent lineage-tracing experiments challenge their existence. Even in light of these lineage-tracing experiments, we suggest that evidence for neogenesis or new islet formation after birth remains strong. Our work has suggested that the pancreatic duct epithelium itself serves as a pool for progenitors for both islet and acinar tissues after birth and into adulthood and, thus, that the duct epithelium can be considered 'facultative stem cells'. We will develop our case for this hypothesis in this perspective.

Vascularisation of transplanted islets is largely established over a 10-day period, with the angiogenesis being mostly derived from recipient precursor elements [1]. This rapid development of blood vessels facilitates the delivery of oxygen and nutrients to the grafts, thereby being critical for optimising insulin production. Several studies indicate that islets transplanted into the diabetic milieu do less well than those placed into a normoglycaemic environment [2±4]. This study explores the hypothesis that the diabetic state interferes with the vascularisation of transplanted islets.The initiation of angiogenesis is presumed to be in part due to local hypoxia with resultant activation of genes critical to the process [5±7]. Some of the factors AbstractAims/hypothesis. The vascularisation of newly transplanted islets originates from the recipients. Because islets transplanted into a diabetic do less well than those transplanted into a euglycaemic environment, we examined the hypothesis that gene expression of angiogenic factors in grafts is delayed in diabetes. These factors include hepatocyte growth factor (HGF) and its receptor c-MET, and urokinase plasminogen activator (uPA) and its receptor uPAR, basic fibroblast growth factor (bFGF), TGF-a and TGFb-1. Methods. Isolated rat islets were studied in vitro under normoxic and hypoxic culture conditions and gene expression was determined with semi-quantitative multiplex RT-PCR. We found that HGF but not c-MET expression was induced by hypoxia in vitro. Using syngeneic Lewis rats, gene expression was also studied in grafts on days 1, 3, 5, 7 and 14 after transplantation.