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The Plastic Pancreas

2013; Elsevier BV; Volume: 26; Issue: 1 Linguagem: Inglês

10.1016/j.devcel.2013.06.013

1878-1551

Ziv Oren, Benjamin Gläser, Yuval Dor,

Diabetes Management and Research

Pancreas homeostasis is based on replication of differentiated cells in order to maintain proper organ size and function under changing physiological demand. Recent studies suggest that acinar cells, the most abundant cell type in the pancreas, are facultative progenitors capable of reverting to embryonic-like multipotent progenitor cells under injury conditions associated with inflammation. In parallel, it is becoming apparent that within the endocrine pancreas, hormone-producing cells can lose or switch their identity under metabolic stress or in response to single gene mutations. This new view of pancreas dynamics suggests interesting links between pancreas regeneration and pathologies including diabetes and pancreatic cancer. Pancreas homeostasis is based on replication of differentiated cells in order to maintain proper organ size and function under changing physiological demand. Recent studies suggest that acinar cells, the most abundant cell type in the pancreas, are facultative progenitors capable of reverting to embryonic-like multipotent progenitor cells under injury conditions associated with inflammation. In parallel, it is becoming apparent that within the endocrine pancreas, hormone-producing cells can lose or switch their identity under metabolic stress or in response to single gene mutations. This new view of pancreas dynamics suggests interesting links between pancreas regeneration and pathologies including diabetes and pancreatic cancer. The presence of adult pancreatic stem cells has been hotly debated for many years. Numerous studies have suggested that during adult life, new endocrine cells form by differentiation of duct cells, budding to generate new islets. However, genetic lineage tracing studies in mice have failed to identify significant interconversion of identity between pancreatic compartments during adult life. In other words, under normal conditions genetically labeled alpha, beta, duct, and acinar cells give rise to, and are generated from, alpha, beta, duct, and acinar cells only (Desai et al., 2007Desai B.M. Oliver-Krasinski J. De Leon D.D. Farzad C. Hong N. Leach S.D. Stoffers D.A. Preexisting pancreatic acinar cells contribute to acinar cell, but not islet beta cell, regeneration.J. Clin. Invest. 2007; 117: 971-977Crossref PubMed Scopus (256) Google Scholar, Dor et al., 2004Dor Y. Brown J. Martinez O.I. Melton D.A. Adult pancreatic beta-cells are formed by self-duplication rather than stem-cell differentiation.Nature. 2004; 429: 41-46Crossref PubMed Scopus (1913) Google Scholar, Herrera, 2000Herrera P.L. Adult insulin- and glucagon-producing cells differentiate from two independent cell lineages.Development. 2000; 127: 2317-2322Crossref PubMed Google Scholar, Kopinke and Murtaugh, 2010Kopinke D. Murtaugh L.C. Exocrine-to-endocrine differentiation is detectable only prior to birth in the uninjured mouse pancreas.BMC Dev. Biol. 2010; 10: 38Crossref PubMed Scopus (90) Google Scholar, Solar et al., 2009Solar M. Cardalda C. Houbracken I. Martín M. Maestro M.A. De Medts N. Xu X. Grau V. Heimberg H. Bouwens L. Ferrer J. 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 (376) Google Scholar), obeying tissue dynamics described by Charles Leblond as "expanding tissues" (Leblond, 1964Leblond, C.P. (1964). Classification of Cell Populations on the Basis of Their Proliferative Behavior. C.C. Congdon, ed. International Symposium on the Control of Cell Division and the Induction of Cancer, pp. 119–150.Google Scholar) or more recently as a "simple duplication" mode of maintenance. These findings, therefore, suggested that stem or progenitor cells in the adult pancreas do not exist. This view has major implications for the future of regenerative therapy in diabetes, because the only potential route for the generation of new beta cells during adult life would thus be replication of differentiated beta cells. In the case of type 1 diabetes, where beta cells are almost totally eliminated by autoimmune destruction, transplantation of induced pluripotent stem cells or embryonic stem cell-derived beta cells would be the only way to a cure. The absence of stem or progenitor cells and transition of cells between differentiated compartments also has implications for the cellular origins of pancreatic cancer: under a "simple duplication" model, pancreatic ductal adenocarcinoma and its precursors (pancreatic intraepithelial neoplasia, or PanIN, lesions), which resemble ducts, are probably derived from ducts. If ducts were indeed the tissue harboring the cell of origin for pancreatic cancer, we would need to understand their biology much better to identify the events that lead to cancer, to search for early diagnostic markers, and more. What remains unaddressed under this framework is whether facultative progenitor cells exist in the adult pancreas: that is, whether "standard" terminally differentiated cells under normal conditions gain progenitor characteristics under specific injury conditions, as has been shown to occur in the liver when injured hepatocytes are prevented from entering the cell cycle (Michalopoulos, 2011Michalopoulos G.K. Liver regeneration: alternative epithelial pathways.Int. J. Biochem. Cell Biol. 2011; 43: 173-179Crossref PubMed Scopus (99) Google Scholar, Shin et al., 2011Shin S. Walton G. Aoki R. Brondell K. Schug J. Fox A. Smirnova O. Dorrell C. Erker L. Chu A.S. et al.Foxl1-Cre-marked adult hepatic progenitors have clonogenic and bilineage differentiation potential.Genes Dev. 2011; 25: 1185-1192Crossref PubMed Scopus (124) Google Scholar). Several lineage tracing studies have examined pancreas cell dynamics after specific injury conditions, for example partial pancreatectomy, pancreatic duct ligation, and partial ablation of beta cells (Dor et al., 2004Dor Y. Brown J. Martinez O.I. Melton D.A. Adult pancreatic beta-cells are formed by self-duplication rather than stem-cell differentiation.Nature. 2004; 429: 41-46Crossref PubMed Scopus (1913) Google Scholar, Nir et al., 2007Nir T. Melton D.A. Dor Y. Recovery from diabetes in mice by beta cell regeneration.J. Clin. Invest. 2007; 117: 2553-2561Crossref PubMed Scopus (479) Google Scholar, Solar et al., 2009Solar M. Cardalda C. Houbracken I. Martín M. Maestro M.A. De Medts N. Xu X. Grau V. Heimberg H. Bouwens L. Ferrer J. 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 (376) Google Scholar). By and large, these studies have not found any evidence for intercompartment transitions. However, proving the negative is always difficult, so controversy on facultative progenitors in the pancreas persists. Recent findings provide solid evidence for the existence of facultative progenitor cells in the adult pancreas and offer a view that may reconcile previous contradicting reports. In 2008, Harry Heimberg's group reported that pancreatic duct ligation (PDL), a century-old surgical procedure that causes the degeneration of acinar cells in the ligated part, leads to the doubling of beta cell mass via the formation of Neurogenin3+ embryonic-like progenitor cells in ducts (Van de Casteele et al., 2013Van de Casteele M. Leuckx G. Baeyens L. Cai Y. Yuchi Y. Coppens V. De Groef S. Eriksson M. Svensson C. Ahlgren U. et al.Neurogenin 3+ cells contribute to β-cell neogenesis and proliferation in injured adult mouse pancreas.Cell Death Dis. 2013; 4: e523Crossref PubMed Scopus (78) Google Scholar, Xu et al., 2008Xu X. D'Hoker J. Stangé G. Bonné S. De Leu N. Xiao X. Van de Casteele M. Mellitzer G. Ling Z. Pipeleers D. et al.Beta cells can be generated from endogenous progenitors in injured adult mouse pancreas.Cell. 2008; 132: 197-207Abstract Full Text Full Text PDF PubMed Scopus (819) Google Scholar). The suggestion that a specific injury to the exocrine pancreas may trigger the embryonic program of beta cell formation led to a surge of genetic lineage tracing studies that directly tested this notion of duct-to-beta-cell reprogramming. However, these efforts failed to reproduce the original findings. Increased beta cell mass after PDL was not seen (Kopp et al., 2011bKopp J.L. Dubois C.L. Schaffer A.E. Hao E. Shih H.P. Seymour P.A. Ma J. Sander M. 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 (349) Google Scholar, Rankin et al., 2013Rankin M.M. Wilbur C.J. Rak K. Shields E.J. Granger A. Kushner J.A. β-cells are not generated in pancreatic duct ligation-induced injury in adult mice.Diabetes. 2013; 62: 1634-1645Crossref PubMed Scopus (89) Google Scholar), and genetic labeling of pre-existing ducts using multiple different promoters (Hnf1beta, Hes1, and Sox9) (Kopinke et al., 2011Kopinke D. Brailsford M. Shea J.E. Leavitt R. Scaife C.L. Murtaugh L.C. Lineage tracing reveals the dynamic contribution of Hes1+ cells to the developing and adult pancreas.Development. 2011; 138: 431-441Crossref PubMed Scopus (156) Google Scholar, Kopp et al., 2011aKopp J.L. Dubois C.L. Hao E. Thorel F. Herrera P.L. Sander M. Progenitor cell domains in the developing and adult pancreas.Cell Cycle. 2011; 10: 1921-1927Crossref PubMed Scopus (70) Google Scholar, Kopp et al., 2011bKopp J.L. Dubois C.L. Schaffer A.E. Hao E. Shih H.P. Seymour P.A. Ma J. Sander M. 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 (349) Google Scholar, Solar et al., 2009Solar M. Cardalda C. Houbracken I. Martín M. Maestro M.A. De Medts N. Xu X. Grau V. Heimberg H. Bouwens L. Ferrer J. 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 (376) Google Scholar) failed to detect lineage-labeled endocrine cells. The exception was a study that used the Carbonic Anhydrase II promoter to drive Cre expression for genetic lineage tracing, where beta cells were found to be labeled after PDL (Inada et al., 2008Inada A. Nienaber C. Katsuta H. Fujitani Y. Levine J. Morita R. Sharma A. Bonner-Weir S. Carbonic anhydrase II-positive pancreatic cells are progenitors for both endocrine and exocrine pancreas after birth.Proc. Natl. Acad. Sci. USA. 2008; 105: 19915-19919Crossref PubMed Scopus (361) Google Scholar). However, in this case Cre-recombinase was not expressed exclusively in duct cells, so the data were inconclusive. In retrospect, these studies might have simply labeled the wrong cells. A recent study from Chris Wright's group may have resolved the puzzle (Pan et al., 2013Pan F.C. Bankaitis E.D. Boyer D. Xu X. Van de Casteele M. Magnuson M.A. Heimberg H. Wright C.V. Spatiotemporal patterns of multipotentiality in Ptf1a-expressing cells during pancreas organogenesis and injury-induced facultative restoration.Development. 2013; 140: 751-764Crossref PubMed Scopus (217) Google Scholar). This study took advantage of a model proposed by Zhou and Melton to explain the growth and branching of the embryonic pancreas (Zhou et al., 2007Zhou Q. Law A.C. Rajagopal J. Anderson W.J. Gray P.A. Melton D.A. A multipotent progenitor domain guides pancreatic organogenesis.Dev. Cell. 2007; 13: 103-114Abstract Full Text Full Text PDF PubMed Scopus (407) Google Scholar). According to this model, early development of the pancreas is based on multipotent progenitor cells residing in the tips of branches. As these progenitors divide, they leave behind "trunk" cells that give rise to duct cells and endocrine cells, and eventually these tip progenitors differentiate only into acinar cells at the ends of ducts. Therefore, differentiated acinar cells represent the most direct progeny of embryonic multipotent progenitor cells. In the new study, differentiated acinar cells in adult mice were permanently labeled using a gene-replacement allele in which the tamoxifen-dependent Cre-recombinase protein was introduced into the Ptf1a locus. As expected, under normal conditions, labeling of Rosa26-YFP-positive cells remained within the acinar compartment in adult mice. Performing the PDL procedure on these mice revealed a striking sequence of events: while many pre-existing acinar cells died off, some acquired the molecular signature of embryonic multipotent progenitor cells at the tips of branches; these progenitors then gave rise either to acinar cells or to apparently authentic duct cells that, similarly to the situation during normal embryonic development, occasionally expressed Neurogenin3 and became hormone-producing cells including beta cells. Interestingly, endocrine differentiation of acinar cells was amplified by targeted chemical ablation of pre-existing beta cells, suggesting physiological regulation of the process. The model emerging is that adult acinar cells, the direct progeny of embryonic multipotent progenitor cells, retain the potential of their ancestors for self-renewal, as well as differentiation into ductal and endocrine cells. Acinar cells, the most abundant cell type in the pancreas and an extremely specialized secretory cell type, might therefore be the long-sought-after facultative progenitor of the pancreas. Notably, a conceptually similar study (Desai et al., 2007Desai B.M. Oliver-Krasinski J. De Leon D.D. Farzad C. Hong N. Leach S.D. Stoffers D.A. Preexisting pancreatic acinar cells contribute to acinar cell, but not islet beta cell, regeneration.J. Clin. Invest. 2007; 117: 971-977Crossref PubMed Scopus (256) Google Scholar) in which acinar cells were labeled using Elastase-CreER did not reveal any acinar-to-endocrine reprogramming after PDL. More work will be required to understand the discrepancy between the two studies, but a likely explanation is the different timescales of observation. While Desai et al. have examined the pancreas up to 24 days after PDL, Pan et al. have observed acinar-to-endocrine reprogramming at 60 days, but not 30 days, after PDL. Interestingly, recent findings in the pancreatic cancer field have suggested that acinar cells are the most likely cellular origins of PanIN lesions and pancreatic ductal adenocarcinoma. Using lineage-specific transgenic expression of mutant Kras, the key oncogenic driver of pancreatic cancer, it was found that acinar cells are the most vulnerable compartment in the pancreas for oncogenic transformation, dramatically more so than duct cells (De La O et al., 2008De La O J.P. Emerson L.L. Goodman J.L. Froebe S.C. Illum B.E. Curtis A.B. Murtaugh L.C. Notch and Kras reprogram pancreatic acinar cells to ductal intraepithelial neoplasia.Proc. Natl. Acad. Sci. USA. 2008; 105: 18907-18912Crossref PubMed Scopus (313) Google Scholar, Habbe et al., 2008Habbe N. Shi G. Meguid R.A. Fendrich V. Esni F. Chen H. Feldmann G. Stoffers D.A. Konieczny S.F. Leach S.D. Maitra A. Spontaneous induction of murine pancreatic intraepithelial neoplasia (mPanIN) by acinar cell targeting of oncogenic Kras in adult mice.Proc. Natl. Acad. Sci. USA. 2008; 105: 18913-18918Crossref PubMed Scopus (301) Google Scholar, Kopp et al., 2012Kopp J.L. von Figura G. Mayes E. Liu F.F. Dubois C.L. Morris 4th, J.P. Pan F.C. Akiyama H. Wright C.V. Jensen K. et al.Identification of Sox9-dependent acinar-to-ductal reprogramming as the principal mechanism for initiation of pancreatic ductal adenocarcinoma.Cancer Cell. 2012; 22: 737-750Abstract Full Text Full Text PDF PubMed Scopus (447) Google Scholar, Maitra and Leach, 2012Maitra A. Leach S.D. Disputed paternity: the uncertain ancestry of pancreatic ductal neoplasia.Cancer Cell. 2012; 22: 701-703Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar). The current working model emphasizes the importance of acinar to ductal metaplasia. In this process, injured acinar cells, for example under inflammatory conditions (pancreatitis), transiently adopt the morphology and gene expression pattern of ductal cells. When combined with a Kras mutation, these cells have a much-increased chance of proceeding to form PanIN lesions, a step toward the development of frank carcinoma. The exact link between neoplastic transformation of acinar cells and their injury-driven dedifferentiation to embryonic-like multipotent progenitors remains to be defined. Thus, plasticity of acinar cells emerges as a tissue feature that is important for regeneration of all pancreatic compartments and that, under the influence of oncogenic signaling, can be diverted to metaplasia and cancer (Figure 1). It is tempting to offer two generalizations here. First, facultative progenitors of the adult pancreas turn out to be the immediate differentiated progeny of embryonic multipotent progenitors; in other tissues in which adult progenitor cells are difficult to identify, the prime suspects might be the most recent progeny of embryonic multipotent progenitor cells. Second, facultative progenitor cells might be the cellular origins of cancer in other organs as well, reconciling the contrasting views that cancer originates from tissue stem cells or from terminally differentiated cells, and linking cancer to aberrant tissue regeneration. In parallel to the advances in understanding exocrine pancreas plasticity, several recent studies have demonstrated that the identity of pancreatic islet hormone-producing cells is not as stable as previously thought (Figure 2). A paper from Pedro Herrera's group reported that after near-total genetic ablation of beta cells, adjacent glucagon-expressing alpha cells spontaneously acquired features of insulin-producing beta cells, effectively transdifferentiating into beta cells (Thorel et al., 2010Thorel F. Népote V. Avril I. Kohno K. Desgraz R. Chera S. Herrera P.L. Conversion of adult pancreatic alpha-cells to beta-cells after extreme beta-cell loss.Nature. 2010; 464: 1149-1154Crossref PubMed Scopus (867) Google Scholar). In addition, several studies have identified specific single gene manipulations that enforce islet cell reprogramming while retaining cells in the endocrine lineage. Forced expression of the transcription factor Pax4 in alpha cells converts these cells into beta-like cells, though with abnormal physiological responses (Collombat et al., 2009Collombat P. Xu X. Ravassard P. Sosa-Pineda B. Dussaud S. Billestrup N. Madsen O.D. Serup P. Heimberg H. Mansouri A. The ectopic expression of Pax4 in the mouse pancreas converts progenitor cells into alpha and subsequently beta cells.Cell. 2009; 138: 449-462Abstract Full Text Full Text PDF PubMed Scopus (432) Google Scholar). In the other direction, deletion of the maintenance DNA methyltransferase 1 (Dnmt1) in beta cells converts these cells to alpha cells (Dhawan et al., 2011Dhawan S. Georgia S. Tschen S.I. Fan G. Bhushan A. Pancreatic β cell identity is maintained by DNA methylation-mediated repression of Arx.Dev. Cell. 2011; 20: 419-429Abstract Full Text Full Text PDF PubMed Scopus (188) Google Scholar); deletion of Pax6 converts adult islet cells to ghrelin-expressing epsilon cells (which are normally absent from postnatal islets) (Hart et al., 2013Hart A.W. Mella S. Mendrychowski J. van Heyningen V. Kleinjan D.A. The developmental regulator Pax6 is essential for maintenance of islet cell function in the adult mouse pancreas.PLoS ONE. 2013; 8: e54173Crossref PubMed Scopus (60) Google Scholar); and deletion of Nkx6.1 can convert early-life beta cells to somatostatin-expressing delta cells (Schaffer et al., 2013Schaffer A.E. Taylor B.L. Benthuysen J.R. Liu J. Thorel F. Yuan W. Jiao Y. Kaestner K.H. Herrera P.L. Magnuson M.A. et al.Nkx6.1 controls a gene regulatory network required for establishing and maintaining pancreatic Beta cell identity.PLoS Genet. 2013; 9: e1003274Crossref PubMed Scopus (158) Google Scholar). Interestingly, forced expression of the key beta cell transcription factor Pdx1 in alpha cells eliminated glucagon expression but did not convert the cells to beta cells; rather, it generated a stable population of "unprogrammed" endocrine cells not expressing any hormone (Yang et al., 2011Yang Y.P. Thorel F. Boyer D.F. Herrera P.L. Wright C.V. Context-specific α- to-β-cell reprogramming by forced Pdx1 expression.Genes Dev. 2011; 25: 1680-1685Crossref PubMed Scopus (154) Google Scholar). It remains to be seen whether conditions can be found that direct such cells to fully functional beta cells. Finally, a recent paper from Accili's group reported that beta-cell-specific deletion of the transcription factor Foxo1, when combined with metabolic stress, causes diabetes and reduction of beta cell mass in adult life. However, lineage tracing showed that beta cells do not undergo apoptosis in this case; rather, they get stripped of their beta cell identity in a process properly termed dedifferentiation and occasionally thereafter redifferentiate into other hormone-producing cell types (Talchai et al., 2012Talchai C. Xuan S. Lin H.V. Sussel L. Accili D. Pancreatic β cell dedifferentiation as a mechanism of diabetic β cell failure.Cell. 2012; 150: 1223-1234Abstract Full Text Full Text PDF PubMed Scopus (962) Google Scholar). The authors of this paper further suggested that beta cell failure in type 2 diabetes might involve beta cell dedifferentiation, and not losses via beta cell death per se. This latter idea awaits validation using genetic lineage tracing, for example in diabetic db/db mice, and other innovative approaches to demonstrate beta cell dedifferentiation in human diabetes. Because beta cells remain alive, it would be theoretically possible to drive them back to their original identity: a new concept of regenerative therapy for diabetes. These findings are somewhat reminiscent of observations in cancers of the endocrine pancreas (pancreatic neuroendocrine tumors, or PNETs). PNETs contain either nonfunctional endocrine cells (maintaining an apparent endocrine cell identity, but not secreting any identifiable hormone) or functioning endocrine cells that can secrete any of several bioactive substances. Secreted substances may include normal islet hormones such as insulin, hormones characteristic of the fetal pancreas such as gastrin, or even substances not known to be produced by islet cells at any stage of development (Klöppel, 2011Klöppel G. Classification and pathology of gastroenteropancreatic neuroendocrine neoplasms.Endocr. Relat. Cancer. 2011; 18: S1-S16Crossref PubMed Scopus (250) Google Scholar). Thus, while beta cells in type 2 diabetes are notorious for not dividing (in diametric opposition to the overgrowth situation in cancer), islet cell dedifferentiation and the acquisition of new endocrine identity might represent deep molecular similarities between islet cell tumors and type 2 diabetes. Finally, the cell of origin of PNET remains unknown. Deletion of the tumor suppressor menin in beta cells or alpha cells causes the formation of insulinomas and glucagonomas (Bertolino et al., 2003Bertolino P. Tong W.M. Herrera P.L. Casse H. Zhang C.X. Wang Z.Q. Pancreatic beta-cell-specific ablation of the multiple endocrine neoplasia type 1 (MEN1) gene causes full penetrance of insulinoma development in mice.Cancer Res. 2003; 63: 4836-4841PubMed Google Scholar, Crabtree et al., 2003Crabtree J.S. Scacheri P.C. Ward J.M. McNally S.R. Swain G.P. Montagna C. Hager J.H. Hanahan D. Edlund H. Magnuson M.A. et al.Of mice and MEN1: Insulinomas in a conditional mouse knockout.Mol. Cell. Biol. 2003; 23: 6075-6085Crossref PubMed Scopus (190) Google Scholar, Lu et al., 2010Lu J. Herrera P.L. Carreira C. Bonnavion R. Seigne C. Calender A. Bertolino P. Zhang C.X. Alpha cell-specific Men1 ablation triggers the transdifferentiation of glucagon-expressing cells and insulinoma development.Gastroenterology. 2010; 138: 1954-1965Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar), supporting an endocrine origin of PNET (interestingly, deletion of menin in alpha cells has generated both glucagonomas and insulinomas, suggesting alpha-to-beta reprogramming during the oncogenic process [Lu et al., 2010Lu J. Herrera P.L. Carreira C. Bonnavion R. Seigne C. Calender A. Bertolino P. Zhang C.X. Alpha cell-specific Men1 ablation triggers the transdifferentiation of glucagon-expressing cells and insulinoma development.Gastroenterology. 2010; 138: 1954-1965Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar]). However, as discussed above for ductal adenocarcinoma, mutating oncogenes or tumor suppressors in specific cell types shows their tumorigenic potential, not the actual origin of naturally arising tumors. Interestingly, it has been speculated that the PNET may in fact originate in the exocrine pancreas and not in mature islets (Heitz et al., 1979Heitz P.U. Kasper M. Polak J.M. Klöppel G. Pathology of the endocrine pancreas.J. Histochem. Cytochem. 1979; 27: 1401-1402Crossref PubMed Scopus (13) Google Scholar, Kamisawa et al., 2002Kamisawa T. Tu Y. Egawa N. Ishiwata J. Tsuruta K. Okamoto A. Hayashi Y. Koike M. Yamaguchi T. Ductal and acinar differentiation in pancreatic endocrine tumors.Dig. Dis. Sci. 2002; 47: 2254-2261Crossref PubMed Scopus (31) Google Scholar, Vortmeyer et al., 2004Vortmeyer A.O. Huang S. Lubensky I. Zhuang Z. Non-islet origin of pancreatic islet cell tumors.J. Clin. Endocrinol. Metab. 2004; 89: 1934-1938Crossref PubMed Scopus (124) Google Scholar). Genetic lineage tracing studies will be required to examine the provocative idea that neuroendocrine tumors, in addition to ductal adenocarcinoma, originate from dedifferentiation of acinar cells. So far, evidence for an acinar origin of pancreatic cancer is indirect, based on forced expression of oncogenic Kras in acinar and other cell compartments, and documenting their relative sensitivity to transformation. A caveat is that there are many more acinar cells than ductal cells or centroacinar cells; it is difficult to take this into account in experiments based on cell-type-specific ectopic expression of an oncogene. In addition, the key experiment, yet to be performed, is to generate a tumor in a manner that is not biased for one compartment or another (e.g., chemical carcinogenesis, or genetic activation of mutant Kras in all pancreatic lineages). In such tumors, the challenge is to identify the cell of origin; in other words, we need to know the actual, not the possible, cell of origin of cancer. This will require some technical innovation to independently express oncogenes and permanently mark a specific lineage. In addition, extrapolating from mouse models to human cancer is dangerous. Innovative approaches would be required to identify the cellular origins of human pancreatic cancer, perhaps relying on stably inherited epigenetic marks. PDL causes the death of many acinar cells, with a fraction of the remaining cells converting to a phenotype similar to embryonic multipotent progenitors. What triggers this dramatic change of identity and potential in acinar cells? Are all acinar cells identical in their potential for such reprogramming? Do human acinar cells behave similarly? Identifying the factor or factors behind this phenomenon may take the field from a somewhat arcane surgical procedure to a new kind of pharmacology. The recent lineage tracing-based demonstration of beta cells formed by acinar cell reprogramming via a ductal intermediate (Pan et al., 2013Pan F.C. Bankaitis E.D. Boyer D. Xu X. Van de Casteele M. Magnuson M.A. Heimberg H. Wright C.V. Spatiotemporal patterns of multipotentiality in Ptf1a-expressing cells during pancreas organogenesis and injury-induced facultative restoration.Development. 2013; 140: 751-764Crossref PubMed Scopus (217) Google Scholar) is exciting, but many important questions remain open. For example, does a similar process occur in humans? Again, innovative approaches would be required to obtain data at a level of confidence that approaches information from genetic lineage tracing studies in mice. Second, does acinar reprogramming have any functional significance, in particular in diabetes? Quantitatively, the effects documented so far after PDL appear to be too small to matter for overall organ function. The issue goes beyond the mere number of beta cells that are formed: to be therapeutically relevant, acinar-derived beta cells must be functional in terms of glucose-stimulated insulin secretion, which remains to be demonstrated. On the positive side, even if plasticity currently represents a minor event, it might be possible to harness and enhance this process for treating diabetes. This extension would require a deep molecular and physiological understanding of acinar-to-endocrine plasticity, translated to pharmacologic tools. What controls the decision of an alpha cell to reprogram into a beta cell? Can other cells perform the same task? Can the process be controlled experimentally? Do all endocrine cells have the potential for conversion? While we still do not fully understand the rules that govern endocrine cell plasticity, the striking similarity in genome-wide chromatin structure between alpha and beta cells might be the basis for the relative ease of intra-islet cell transitions (Bramswig et al., 2013Bramswig N.C. Everett L.J. Schug J. Dorrell C. Liu C. Luo Y. Streeter P.R. Naji A. Grompe M. Kaestner K.H. Epigenomic plasticity enables human pancreatic α to β cell reprogramming.J. Clin. Invest. 2013; 123: 1275-1284Crossref PubMed Scopus (299) Google Scholar). The beta cell ablation system developed by Herrera and colleagues (Thorel et al., 2010Thorel F. Népote V. Avril I. Kohno K. Desgraz R. Chera S. Herrera P.L. Conversion of adult pancreatic alpha-cells to beta-cells after extreme beta-cell loss.Nature. 2010; 464: 1149-1154Crossref PubMed Scopus (867) Google Scholar) provides a good experimental platform to address many of these questions. The view that beta cell identity is a fragile state that can be disrupted by metabolic stress is tantalizing because it suggests that beta cell dedifferentiation rather than beta cell death might be the predominant cause of beta cell failure in diabetes (most likely in type 2 diabetes but perhaps taking place even in type 1 diabetes). If dedifferentiated beta cells (and beta cells that went further to acquire new endocrine identities) could be pushed back to their functional mature state, diabetes might be reversed. It remains to be seen whether such a return journey can be accomplished. Understanding the determinants of beta cell identity, dedifferentiation, and—potentially—redifferentiation is a fascinating challenge for the near future. Finally, the recent findings suggest a speculative unifying view of the link between adult pancreas plasticity and human disease. In the case of the exocrine pancreas, is it possible that the same genes and factors that place acinar cells as facultative progenitors, potentially supporting pancreas regeneration, render these cells particularly susceptible to oncogenic transformation? In the case of the endocrine pancreas, is it possible that dedifferentiation is a theme common to both type 2 diabetes and islet cell tumors? We thank Christopher Wright, Klaus Kaestner, Ben Stanger, Lori Sussel and Doris Stoffers for stimulating discussions and comments. Research in our laboratories is funded by grants from the Beta-Cell Biology Consortium, the Juvenile Diabetes Research Foundation, the European Research Council, EU/FP7 (BetaCellTherapy, grant 241883), the Helmsley trust, the Dutch friends of Hebrew University, the Diabetes Onderzoek Nederland foundation, and the I-CORE Program of the Planning and Budgeting Committee and The Israel Science Foundation #41.11. O.Z. is a New York Stem Cell Foundation-Druckenmiller Fellow.