Control of Cell Identity in Pancreas Development and Regeneration
2013; Elsevier BV; Volume: 144; Issue: 6 Linguagem: Inglês
10.1053/j.gastro.2013.01.074
ISSN1528-0012
AutoresBen Z. Stanger, Matthias Hebrok,
Tópico(s)Diet, Metabolism, and Disease
ResumoThe endocrine and exocrine cells in the adult pancreas are not static, but can change their differentiation state in response to injury or stress. This concept of cells in flux means that there may be ways to generate certain types of cells (such as insulin-producing β-cells) and prevent formation of others (such as transformed neoplastic cells). We review different aspects of cell identity in the pancreas, discussing how cells achieve their identity during embryonic development and maturation, and how this identity remains plastic, even in the adult pancreas. The endocrine and exocrine cells in the adult pancreas are not static, but can change their differentiation state in response to injury or stress. This concept of cells in flux means that there may be ways to generate certain types of cells (such as insulin-producing β-cells) and prevent formation of others (such as transformed neoplastic cells). We review different aspects of cell identity in the pancreas, discussing how cells achieve their identity during embryonic development and maturation, and how this identity remains plastic, even in the adult pancreas. View Large Image Figure ViewerDownload Hi-res image Download (PPT) In mammals, the pancreas regulates the response to feeding via an exocrine compartment, which produces and releases enzymes that digest proteins and lipids, and an endocrine compartment, which controls blood glucose levels by producing hormones such as insulin and glucagon. Even before food enters the mouth, its smell induces secretion of digestive enzymes1Pavlov I. The work of the digestive glands. Charles Griffin, London, UK1902Google Scholar and insulin2Teff K.L. How neural mediation of anticipatory and compensatory insulin release helps us tolerate food.Physiol Behav. 2011; 103: 44-50Crossref PubMed Scopus (99) Google Scholar during the so-called cephalic phase of digestion—a signaling pathway that begins in the brain and is transmitted via the vagus nerve. As food enters the digestive tract, digestive enzymes are secreted into the intestinal lumen and glucose-regulating hormones are released into the blood, resulting in a coordinated metabolic response. This response evolved in multicellular organisms, and precursors of the mammalian pancreas can be traced far back in the phylogenetic tree. Worms and protochordates have gut cells that produce insulin-like peptides, whereas Drosophila have similar peptide-producing cells in the pars intracerebralis of the brain.3Heller R.S. The comparative anatomy of islets.Adv Exp Med Biol. 2010; 654: 21-37Crossref PubMed Scopus (23) Google Scholar Among vertebrates, the hagfish, which has insulin-producing cells near the bile duct, is the most primitive vertebrate to have a pancreas-like structure. Ancient sharks have a tissue that more closely resembles the mammalian pancreas, containing a mixture of endocrine and exocrine cells, and more advanced fish can have 2 distinct types of pancreata. Teleosts (such as zebrafish) have primary islets (also called Brockman's bodies), which are composed primarily of endocrine tissue, and also have secondary islets, which are embedded within a diffuse exocrine network. During the evolution of amphibians and mammals, exocrine tissue came to occupy an increasingly large fraction of the pancreatic mass, whereas endocrine cells began to form well-defined, encapsulated islets (Figure 1A). The fact that isolated insulin-producing cells appeared before exocrine tissue led to the proposal that β-cells are phylogenetic precursors of the mammalian pancreas.4Madsen O.D. Pancreas phylogeny and ontogeny in relation to a 'pancreatic stem cell'.C R Biol. 2007; 330: 534-537Crossref PubMed Scopus (24) Google Scholar The exocrine pancreas might have evolved in higher organisms via activity of the pancreas-specific transcription factor (Ptf)1, which regulates expression of exocrine-specific genes, in endocrine tissues. In support of this model, down-regulation of Ptf1a in adult zebrafish exocrine cells results in their conversion to endocrine-like cells.5Hesselson D. Anderson R.M. Stainier D.Y. Suppression of Ptf1a activity induces acinar-to-endocrine conversion.Curr Biol. 2011; 21: 712-717Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar The developmental origin of β-cells is another interesting feature of pancreatic phylogeny. Remarkably, in vertebrates, insulin-producing cells develop from endoderm, whereas in flies they develop from ectoderm. Because there is significant overlap among β-cell and neuronal signaling pathways,6Atouf F. Czernichow P. Scharfmann R. Expression of neuronal traits in pancreatic beta cells Implication of neuron-restrictive silencing factor/repressor element silencing transcription factor, a neuron-restrictive silencer.J Biol Chem. 1997; 272: 1929-1934Crossref PubMed Scopus (159) Google Scholar it is possible that during vertebrate evolution, central nervous system signaling pathways also were used to generate β-cells in the digestive tract.7Wang S. Tulina N. Carlin D.L. et al.The origin of islet-like cells in Drosophila identifies parallels to the vertebrate endocrine axis.Proc Natl Acad Sci U S A. 2007; 104: 19873-19878Crossref PubMed Scopus (75) Google Scholar In other words, a discrete regulatory module may govern endocrine identity. Based on the evolution of the pancreas, it is possible that this plasticity is related to an ancient and portable endocrine program, a module that also may underlie the high degree of cellular plasticity that is seen in the adult pancreas. The endoderm gives rise to the tissues that line the gastrointestinal tract; specification of naive cells requires precise integration of signals from several pathways to ensure proper alignment of organ rudiments along the anterior–posterior axis. There is evidence that production of fibroblast growth factor (Fgf)4 by mesodermal cells posteriorizes endoderm in a concentration-dependent manner.8Wells J.M. Melton D.A. Early mouse endoderm is patterned by soluble factors from adjacent germ layers.Development. 2000; 127: 1563-1572PubMed Google Scholar Similarly, retinoic acid (RA) signaling has been shown in several species, including mice and zebrafish, to control anterior−posterior patterning of gut organs and promote pancreatic identity.9Bayha E. Jorgensen M.C. Serup P. et al.Retinoic acid signaling organizes endodermal organ specification along the entire antero-posterior axis.PLoS One. 2009; 4: e5845Crossref PubMed Scopus (95) Google Scholar, 10Stafford D. White R.J. Kinkel M.D. et al.Retinoids signal directly to zebrafish endoderm to specify insulin-expressing beta-cells.Development. 2006; 133: 949-956Crossref PubMed Scopus (106) Google Scholar The pancreas is unique among gastrointestinal organs in that it derives from the dorsal and ventral portions of the endoderm.11Slack J.M.W. Developmental biology of the pancreas.Development. 1995; 121: 1569-1580Crossref PubMed Google Scholar The ventral part of the pancreas arises from anterior endoderm close to the liver anlage, whereas the dorsal pancreas forms from posterior endoderm cells; each part interacts with different surrounding tissues during development. The first sign of the dorsal pancreas in mice is an epithelial thickening of the dorsal endodermal sheet at around embryonic day 9. Before that stage, the uncommitted endoderm cells of the forming gut tube receive signals from the notochord, an embryonic mesoderm signaling center that provides informational cues to the overlying neural tube and underlying endoderm.12Kim S.K. Hebrok M. Melton D.A. Notochord to endoderm signaling is required for pancreas development.Development. 1997; 124: 4243-4252Crossref PubMed Google Scholar Over time, the notochord is displaced by the dorsal aorta, which separates the endoderm from the notochord. Signals from the notochord such as activin and Fgf block expression of sonic hedgehog, a member of the hedgehog (Hh) signaling family that regulates stomach and duodenal organ formation.13Hebrok M. Hedgehog signaling in pancreas development.Mech Dev. 2003; 20: 45-57Crossref Scopus (122) Google Scholar, 14Hebrok M. Kim S.K. Melton D.A. Notochord repression of endodermal Sonic hedgehog permits pancreas development.Genes Dev. 1998; 12: 1705-1713Crossref PubMed Scopus (507) Google Scholar Sonic Hh production in pancreas epithelium generates a molecular boundary and controls organ specification at the foregut−midgut border. Signals generated by the aortic endothelium promote dorsal bud outgrowth and eventually are replaced by the coalescence of mesenchymal cells around the evaginating epithelium of the pancreas.15Lammert E. Cleaver O. Melton D. Induction of pancreatic differentiation by signals from blood vessels.Science. 2001; V294: 564-567Crossref Scopus (891) Google Scholar, 16Landsman L. Nijagal A. Whitchurch T.J. et al.Pancreatic mesenchyme regulates epithelial organogenesis throughout development.PLoS Biol. 2011; 9: e1001143Crossref PubMed Scopus (110) Google Scholar, 17Yoshitomi H. Zaret K.S. Endothelial cell interactions initiate dorsal pancreas development by selectively inducing the transcription factor Ptf1a.Development. 2004; 131: 807-817Crossref PubMed Scopus (214) Google Scholar The ventral pancreas gives rise to 2 distinct buds in mammals. One of these buds regresses soon after evagination, whereas the remaining bud branches into the surrounding mesenchyme. The endoderm tissues that give rise to the ventral pancreas buds are in direct contact with the lateral plate mesoderm; this tissue provides signals that initiate pancreas organogenesis at a specific point along the anterior−posterior axis. Signaling by activins, RA, and bone morphogenetic protein 7 induces the expression of pancreatic markers in ventral endoderm, similar to the roles of activin and RA in the dorsal bud.18Kumar M. Jordan N. Melton D. et al.Signals from lateral plate mesoderm instruct endoderm toward a pancreatic fate.Dev Biol. 2003; 259: 109-122Crossref PubMed Scopus (202) Google Scholar Signals from the cardiac mesenchyme and septum transversum further distinguish the liver and pancreas anlagen in the ventral endoderm sheet. Increased Fgf signaling from the cardiac mesenchyme promotes differentiation of liver, instead of pancreas, which is reinforced by a delicate balance of transforming growth factor-β, bone morphogenetic protein, and FGF signals from the septum transversum.19Wandzioch E. Zaret K.S. Dynamic signaling network for the specification of embryonic pancreas and liver progenitors.Science. 2009; 324: 1707-1710Crossref PubMed Scopus (201) Google Scholar Therefore, interactions among different signaling pathways from the tissues that surround the ventral pancreas regulate its formation. After organ specification, the pancreas epithelium thickens and eventually protrudes into the surrounding mesenchyme. Although researchers used to believe that the pancreas developed from a dense, cohesive epithelial bud that extended and branched, formation of a microlumen has been included in the process.20Villasenor A. Chong D.C. Henkemeyer M. et al.Epithelial dynamics of pancreatic branching morphogenesis.Development. 2010; 137: 4295-4305Crossref PubMed Scopus (169) Google Scholar Detailed analyses of morphogenesis revealed that the organ forms from a single-layer epithelium that undergoes stratification; the inner cells develop without direct contact with either the primary central lumen or the basement membrane. Multiple microlumens form within the epithelium, eventually fusing to generate a single lumen with ductal tubes that line the internal space. There is increasing evidence that the surrounding mesenchyme promotes morphogenesis of the epithelial structures. Signaling by ephrin B2, expressed in pancreatic mesenchyme, through its receptor, EphB, on epithelial cells is required for structural changes, including the development of the microlumens.20Villasenor A. Chong D.C. Henkemeyer M. et al.Epithelial dynamics of pancreatic branching morphogenesis.Development. 2010; 137: 4295-4305Crossref PubMed Scopus (169) Google Scholar The fusion of microlumens is followed by the segregation of the epithelial structures into distal tip and proximal trunk regions—morphologic changes that precede the differentiation of specific cell lineages within the pancreatic epithelium. Carefully timed morphogenetic movements of the pancreas epithelium therefore precede cell lineage specification during the early stages of pancreas formation. The diverse endodermal cell types of the adult pancreas include digestive enzyme–producing acinar cells, duct cells that form the lumen through which acinar enzymes are transported toward the duodenum, centro-acinar cells that connect duct and acini, and hormone-producing endocrine cells located in islets of Langerhans. All of these cell types derive from multipotent progenitor cells present within the pancreas epithelium at early stages of development. Much of what we know about the lineage relationships among the different cell types has been determined using transgenic mice that allow for labeling of specific cell subsets during development. These studies have provided important information about the stepwise progression of endodermal cells within the endodermal sheet to lineage-restricted, multipotent progenitors to fully differentiated cells with specialized functions in the adult organ. Acinar cells are highly specialized and organized similar to bunches of grapes at the end of small ducts; they make up the bulk of the mature pancreas. They produce more than 20 different enzymes, including DNAses, proteinases, and lipases, which are required for digestion in the duodenum. The first molecular feature of future acinar cells is expression of the digestive enzyme carboxypeptidase A1 (Cpa1) in cells at the distal tips of the branching epithelium. Interestingly, when Cpa1 expression is first detected, these distal cells still have the potential to differentiate into all pancreatic lineages, including acinar, duct, and endocrine cells.21Zhou Q. Law A.C. Rajagopal J. et al.A multipotent progenitor domain guides pancreatic organogenesis.Dev Cell. 2007; 13: 103-114Abstract Full Text Full Text PDF PubMed Scopus (424) Google Scholar Subsequently, when the epithelial tree expands, the distal tip cells commit toward the acinar lineage through activity of a trimeric transcription complex comprising Ptf1a, recombination signal binding protein for immunoglobulin-κ J region-like (Rbpj-l), and a common E-protein.22Masui T. Long Q. Beres T.M. et al.Early pancreatic development requires the vertebrate suppressor of hairless (RBPJ) in the PTF1 bHLH complex.Genes Dev. 2007; 21: 2629-2643Crossref PubMed Scopus (127) Google Scholar This complex regulates the expression of genes that encode digestive enzymes and genes required for acinar cell function.23Masui T. Swift G.H. Deering T. et al.Replacement of Rbpj with Rbpjl in the PTF1 complex controls the final maturation of pancreatic acinar cells.Gastroenterology. 2010; 139: 270-280Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar Acinar cell development and expansion is guided by the temporal activities of embryonic signaling pathways, including Notch and Wnt signaling. Inhibition of the Notch signaling mediator Rbpj-k in pancreas epithelium reduces, but does not completely eliminate, acinar cell development,24Fujikura J. Hosoda K. Iwakura H. et al.Notch/Rbp-j signaling prevents premature endocrine and ductal cell differentiation in the pancreas.Cell Metab. 2006; 3: 59-65Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar probably because of its negative effects on the expansion of multipotent pancreas progenitors. Sustained Notch signaling compromises differentiation of acinar cells, at least in part by inhibiting Ptf1a-mediated activation of acinar genes.25Esni F. Ghosh B. Biankin A.V. et al.Notch inhibits Ptf1 function and acinar cell differentiation in developing mouse and zebrafish pancreas.Development. 2004; 131: 4213-4224Crossref PubMed Scopus (183) Google Scholar Increased Hh signaling in embryonic pancreas also compromises expansion of the epithelial cells that form the endocrine and exocrine compartments, including acinar cells.26Cervantes S. Lau J. Cano D.A. et al.Primary cilia regulate Gli/Hedgehog activation in pancreas.Proc Natl Acad Sci U S A. 2010; 107: 10109-10114Crossref PubMed Scopus (53) Google Scholar Canonical Wnt signaling, mediated by β-catenin, is essential for the development of pancreatic acinar cells; sustained activation of the pathway promotes acinar cell proliferation.27Heiser P.W. Lau J. Taketo M.M. et al.Stabilization of beta-catenin impacts pancreas growth.Development. 2006; 133: 2023-2032Crossref PubMed Scopus (198) Google Scholar, 28Murtaugh L.C. Law A.C. Dor Y. et al.Beta-catenin is essential for pancreatic acinar but not islet development.Development. 2005; 132: 4663-4674Crossref PubMed Scopus (198) Google Scholar, 29Strom A. Bonal C. Ashery-Padan R. et al.Unique mechanisms of growth regulation and tumor suppression upon Apc inactivation in the pancreas.Development. 2007; 134: 2719-2725Crossref PubMed Scopus (54) Google Scholar More recent studies have indicated that β-catenin does not control survival or functions of mature acinar cells, but is required for proliferation and regeneration of acinar cells upon injury.30Keefe M.D. Wang H. De La O.J. et al.Beta-catenin is selectively required for the expansion and regeneration of mature pancreatic acinar cells in mice.Dis Model Mech. 2012; 5: 503-514Crossref PubMed Scopus (51) Google Scholar, 31Morris 4th, J.P. Cano D.A. Sekine S. et al.Beta-catenin blocks Kras-dependent reprogramming of acini into pancreatic cancer precursor lesions in mice.J Clin Invest. 2010; 120: 508-520Crossref PubMed Scopus (297) Google Scholar Pancreatic endocrine and duct cells also derive from the multipotent progenitor cells located within the budding epithelium. In contrast to acinar cells, which remain at the distal tips, endocrine and duct progenitors segregate from their acinar counterparts to localize to epithelial cords. The mechanisms by which the duct and endocrine progenitors are generated and separate from acinar progenitors are being investigated. Early models proposed that duct and endocrine progenitors separated from the distal tip cells to form the stalk or trunk of the epithelial tree.21Zhou Q. Law A.C. Rajagopal J. et al.A multipotent progenitor domain guides pancreatic organogenesis.Dev Cell. 2007; 13: 103-114Abstract Full Text Full Text PDF PubMed Scopus (424) Google Scholar This model was based on conventional budding, extension, and branching patterns observed in other epithelial organs, and supported by real-time imaging of morphogenetic events in cultured pancreas rudiments.32Puri S. Hebrok M. Dynamics of embryonic pancreas development using real-time imaging.Dev Biol. 2007; 306: 82-93Crossref PubMed Scopus (67) Google Scholar As described earlier, more recent studies have indicated the formation of an epithelial plexus, in which transient epithelial stratification is followed by de novo tubulogenesis, mediated through microlumen condensation.20Villasenor A. Chong D.C. Henkemeyer M. et al.Epithelial dynamics of pancreatic branching morphogenesis.Development. 2010; 137: 4295-4305Crossref PubMed Scopus (169) Google Scholar This model introduces a more complex process in which profound changes in cell shape and organization promote the development of the branching epithelium. Studies are needed to determine the dynamics by which distal acinar-committed cells would become distinct from endocrine and duct progenitors. Most current models support the concept of a temporal restriction in cell differentiation potential, mirrored and promoted by differential expression of differentiation markers in various multipotent and committed cell populations. For example, although the distal multipotent cells are Pdx1+, Ptf1a+, Cpa1+, and cMychigh,14Hebrok M. Kim S.K. Melton D.A. Notochord repression of endodermal Sonic hedgehog permits pancreas development.Genes Dev. 1998; 12: 1705-1713Crossref PubMed Scopus (507) Google Scholar the emerging duct and endocrine restricted cells are Sox9+, Hnf1β+, Foxa2+, and Nkx6.1+.33Kopp J.L. Dubois C.L. Schaffer A.E. et al.Sox9+ ductal cells are multipotent progenitors throughout development but do not produce new endocrine cells in the normal or injured adult pancreas.Development. 2011; 138: 653-665Crossref PubMed Scopus (369) Google Scholar, 34Solar M. Cardalda C. Houbracken I. et al.Pancreatic exocrine duct cells give rise to insulin-producing beta cells during embryogenesis but not after birth.Dev Cell. 2009; 17: 849-860Abstract Full Text Full Text PDF PubMed Scopus (389) Google Scholar Between embryonic days 13.5 and 15.5 (a period called the secondary transition), endocrine progenitors within the trunk epithelium form by reducing expression of Sox9 and Hnf1b. Concomitantly, neurogenin-3 (Ngn3), a transcription factor that is required for endocrine cell development, is expressed transiently. Its up-regulation results in separation of endocrine cells from the duct lineage. Endocrine cells become separated from the trunk epithelium and cluster to form aggregates, eventually maturing into islets of Langerhans. Duct progenitors within the trunk retain Hnf1b and Sox9 expression and form a mature system of tubes that connect enzyme-producing acinar cells with the duodenum. If basic science discoveries are to be developed into therapeutic treatments, the experimental models we use must have relevance to human biology. It is therefore appropriate to ask whether the lineage relationships and morphologic and transcriptional changes observed during pancreatic development in rodents are similar to those that occur during human development. Surprisingly, there appears to be a great deal of overlap. One of the most obvious differences pertains to overall organ morphology. Similar to its rodent counterpart, the human pancreas emerges from ventral and dorsal endoderm buds that arise at as early as 5 weeks' gestation. In human beings these 2 buds merge into a single organ a week later, ultimately coming to reside in the retroperitoneal space. By contrast, the mouse pancreas is spread more diffusely along the intestinal mesentery within the abdominal cavity. The species also differ in islet organization and composition. In murine islets, β-cells are found in the center of the islet, where they comprise 77% of the cells. In human islets, β-cells are interspersed with other endocrine cells and comprise 55% of the cells in the islet.35Cabrera O. Berman D.M. Kenyon N.S. et al.The unique cytoarchitecture of human pancreatic islets has implications for islet cell function.Proc Natl Acad Sci U S A. 2006; 103: 2334-2339Crossref PubMed Scopus (968) Google Scholar The transcription factors that regulate pancreas development seem to be conserved between rodents and human beings. Mutations in PDX1 and PTF1A lead to pancreas agenesis in human beings, as they do in mice,36Sellick G.S. Barker K.T. Stolte-Dijkstra I. et al.Mutations in PTF1A cause pancreatic and cerebellar agenesis.Nat Genet. 2004; 36: 1301-1305Crossref PubMed Scopus (375) Google Scholar, 37Stoffers D.A. Zinkin N.T. Stanojevic V. et al.Pancreatic agenesis attributable to a single nucleotide deletion in the human IPF1 gene coding sequence.Nat Genet. 1997; 15: 106-110Crossref PubMed Scopus (962) Google Scholar and haploinsufficiency for SOX9 results in Campomelic dysplasia, associated with abnormal pancreatic morphology and perturbed islet composition.38Piper K. Ball S.G. Keeling J.W. et al.Novel SOX9 expression during human pancreas development correlates to abnormalities in Campomelic dysplasia.Mech Dev. 2002; 116: 223-226Crossref PubMed Scopus (77) Google Scholar The finding that individuals with mutations in Ngn3 lack intestinal endocrine cells but do not develop diabetes led to the proposal that human beings have a different or possibly redundant factor that controls pancreatic endocrine development.39Wang J. Cortina G. Wu S.V. et al.Mutant neurogenin-3 in congenital malabsorptive diarrhea.N Engl J Med. 2006; 355: 270-280Crossref PubMed Scopus (255) Google Scholar However, subsequent analysis showed that the Ngn3 mutations identified in human patients are hypomorphic and permit sufficient islet development to maintain euglycemia.40Jensen J.N. Rosenberg L.C. Hecksher-Sorensen J. et al.Mutant neurogenin-3 in congenital malabsorptive diarrhea.N Engl J Med. 2007; 356: 1781-1782Crossref PubMed Scopus (40) Google Scholar Human beings and mice therefore seem to have similar molecular pathways that control cell identity in the pancreas. More than 50 years ago, Waddington coined the term epigenetics to describe a process whereby stable (and heritable) changes in gene expression affect steps in cellular differentiation.41Goldberg A.D. Allis C.D. Bernstein E. Epigenetics: a landscape takes shape.Cell. 2007; 128: 635-638Abstract Full Text Full Text PDF PubMed Scopus (1842) Google Scholar According to this view, differentiation represents a stable state. It might seem that substantial energy would be required to move a cell from one differentiated state to another. However, there is increasing evidence that the boundaries that maintain cellular identity can be overcome easily, which has important implications for developmental biology. Much of this emerging evidence comes from studies in the pancreas (Figure 2). One of the first pieces of evidence that maintenance of cell identity requires active regulation of gene expression was the finding that deletion of Pdx1 from postnatal islets resulted in loss of the β-cells phenotype.42Ahlgren U. Jonsson J. Jonsson L. et al.Beta-cell-specific inactivation of the mouse Ipf1/Pdx1 gene results in loss of the beta-cell phenotype and maturity onset diabetes.Genes Dev. 1998; 12: 1763-1768Crossref PubMed Scopus (795) Google Scholar That study reported an increase in α-cells in the islets, although it was unclear whether Pdx1 resulted in conversion of β-cell progenitors to α-cells or whether there was a compensatory increase in α-cell numbers. More recently, Yang et al43Yang Y.P. Thorel F. Boyer D.F. et al.Context-specific alpha- to-beta-cell reprogramming by forced Pdx1 expression.Genes Dev. 2011; 25: 1680-1685Crossref PubMed Scopus (164) Google Scholar showed that ectopic expression of Pdx1 in endocrine progenitor cells causes them to adopt a β-cell fate, indicating that Pdx1 is a β-cell specification or maintenance factor. DNA methylation status also seems to maintain the identity of β-cells in the adult pancreas. In adult β-cells, the promoter of the Aristaless homeobox gene (Arx) is methylated, resulting in its transcriptional inactivation, which also requires NK2 homeobox 2.44Papizan J.B. Singer R.A. Tschen S.I. et al.Nkx2.2 repressor complex regulates islet beta-cell specification and prevents beta-to-alpha-cell reprogramming.Genes Dev. 2011; 25: 2291-2305Crossref PubMed Scopus (150) Google Scholar Deletion of DNA (cytosine-5-)-methyltransferase 1, which maintains previously established methylation patterns on DNA, causes loss of β-cells in mice.45Dhawan S. Georgia S. Tschen S.I. et al.Pancreatic beta cell identity is maintained by DNA methylation-mediated repression of Arx.Dev Cell. 2011; 20: 419-429Abstract Full Text Full Text PDF PubMed Scopus (198) Google Scholar The mechanism for this loss of β-cells appears to involve reactivation of Arx; transgenic expression of Arx in β-cells causes their conversion to α-cells.46Collombat P. Hecksher-Sorensen J. Krull J. et al.Embryonic endocrine pancreas and mature beta cells acquire alpha and PP cell phenotypes upon Arx misexpression.J Clin Invest. 2007; 117: 961-970Crossref PubMed Scopus (216) Google Scholar Furthermore, post-natal antagonism of Ptf1a leads to the conversion of exocrine cells into endocrine-like cells.5Hesselson D. Anderson R.M. Stainier D.Y. Suppression of Ptf1a activity induces acinar-to-endocrine conversion.Curr Biol. 2011; 21: 712-717Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar Taken together, these studies indicate that pancreatic cell identity must be actively maintained, either through transcription factor expression, chromatin modification, or a combination of these. These findings provide important information for exploring changes in cell identity during injury or after the expression of various reprogramming factors. As the body's reservoir for proteases and lipases, the pancreas is prone to injury from the inadvertent release and activation of these enzymes. Under physiological conditions, enzyme activation is prevented by complex mechanisms in which enzymes are produced as inactive zymogens that become activated only upon entry into the intestinal lumen. However, bypass of these protective mechanisms can lead to a vicious cycle of enzyme autoactivation and acute pancreatitis. Pancreatic injury can be caused by obstruction of the pancreatic ducts (by gallstones or tumors), toxins, drugs, and less common causes. Injury is associated with death of acinar cells and neighboring islets, and can result in transient hyperglycemia. Remarkably, if the cycle of injury and autoactivation is disrupted, the pancreas can fully recover its normal histology and function. A number of animal models have been developed to study the various forms of pancreatitis.47Chan Y.C. Leung P.S. Acute pancreatitis: animal models and recent advances in basic research.Pancreas. 2007; 34: 1-14Crossref PubMed Scopus (143) Google Scholar Mice injected with the cholecystokinin analog cerulein, which promotes secretion of digestive enzymes, are widely used (partly for
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