review of literature on clinical pancreatology - The Pancreapedia

PANCREATIC DEVELOPMENT, EMBRYOLOGY and ANATOMYRegenerative medicine, including cell-replacement strategies, may have an important role inthe treatment <strong>of</strong> type 1 and type 2 diabetes, both <strong>of</strong> which are associated with decreasedislet cell mass. To date, significant progress has been made in deriving insulin-secretingbeta-like cells from human ES (embryonic stem) cells. However, the cells are not fullydifferentiated, and there is a long way to go before they could be used as a replenishablesupply <strong>of</strong> insulin-secreting beta-cells for transplantation. For this reason, adult pancreaticstem cells are seen as an alternative source that could be expanded and differentiated exvivo, or induced to form new islets in situ. In one issue <strong>of</strong> the Biochemical Journal, Mato et al.used drug selection to purify a population <strong>of</strong> stellate cells from explant cultures <strong>of</strong> pancreasfrom lactating rats. The selected cells express some stem-cell markers and can be grown forover 2 years as a fibroblast-like monolayer. When plated on extracellular matrix, along with acocktail <strong>of</strong> growth factors that included insulin, transferrin, selenium and the GLP-1(glucagon-like peptide-1) analogue exendin-4, the cells differentiated into cells thatexpressed many <strong>of</strong> the phenotypic markers characteristic <strong>of</strong> a beta-cell, and exhibited aninsulin-secretory response, albeit weak, to glucose. The ability to purify this cell populationopens up the possibility <strong>of</strong> unravelling the mechanisms that control self-renewal anddifferentiation <strong>of</strong> pancreatic cells that share some <strong>of</strong> the properties <strong>of</strong> stem cells [105].Factors influencing developmentRegenerating gene IPancreatic regenerating gene I (reg I) has been implicated in cellular differentiation. Acinarcells can transdifferentiate into other pancreatic-derived cells, and it was postulated thatchanges in intracellular levels <strong>of</strong> reg I would affect the state <strong>of</strong> differentiation transfectedAR42J cells with a plasmid containing the entire coding sequence <strong>of</strong> reg I and isolatedclones with complementary DNA in sense (SS) or antisense (AS) orientation. It was foundthat in acinar cells, reg I overexpression is linked to acinar cell differentiation, whereasinhibition <strong>of</strong> reg I leads to beta cell and possibly ductal phenotype. Reg I expression in acinarcells is important in maintaining pancreatic cell lineage, and when decreased, cells candedifferentiate and move toward becoming other pancreatic cells [106].Transforming growth factor-beta (TGF-beta)Studies <strong>of</strong> the formation <strong>of</strong> pancreas and liver progenitors have focused on individualinductive signals and cellular responses. Here, it was investigated how bone morphogeneticprotein, transforming growth factor-beta (TGF-beta), and fibroblast growth factor signalingpathways converge on the earliest genes that elicit pancreas and liver induction in mouseembryos. The inductive network was found to be dynamic; it changed within hours. Differentsignals functioned in parallel to induce different early genes, and two permutations <strong>of</strong> signalsinduced liver progenitor domains, which revealed flexibility in cell programming. Also, thespecification <strong>of</strong> pancreas and liver progenitors was restricted by the TGF-beta pathway.These findings may enhance progenitor cell specification from stem cells for biomedicalpurposes and can help explain incomplete programming in stem cell differentiation protocols[107].Islet neogenesis-associated proteinEfforts to cure diabetes are now focused on restoring a physiologically-regulated population<strong>of</strong> insulin-producing cells to the patient. A number <strong>of</strong> animal models <strong>of</strong> beta cell regeneration