Pancreatic Epithelial Cells


(Journal Article): Beta-cell differentiation from nonendocrine epithelial cells of the adult human pancreas
 
Hao E, Tyrberg B, Itkin-Ansari P, Lakey JR, Geron I, Monosov EZ, Barcova M, Mercola M, Levine F (Rebecca and John Moores UCSD Cancer Center, University of California San Diego, 9500 Gilman Drive, MC 0816, La Jolla, California 92093, USA., flevine@ucsd.edu )
 
IN: Nat Med 2006; 12(3):310-316
Impact Factor(s) of Nat Med: 28.878 (2005), 31.223 (2004), 30.55 (2003), 28.74 (2002), 27.906 (2001)

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ABSTRACT: The nature and even existence of adult pancreatic endocrine stem or progenitor cells is a subject of controversy in the field of beta-cell replacement for diabetes. One place to search for such cells is in the nonendocrine fraction of cells that remain after islet isolation, which consist of a mixture of epithelia and mesenchyme. Culture in G418 resulted in elimination of the mesenchymal cells, leaving a highly purified population of nonendocrine pancreatic epithelial cells (NEPECs). To evaluate their differentiation potential, NEPECs were heritably marked and transplanted under the kidney capsule of immunodeficient mice. When cotransplanted with fetal pancreatic cells, NEPECs were capable of endocrine differentiation. We found no evidence of beta-cell replication or cell fusion that could have explained the appearance of insulin positive cells from a source other than NEPECs. Nonendocrine-to-endocrine differentiation of NEPECs supports the existence of endocrine stem or progenitor cells within the epithelial compartment of the adult human pancreas.

TYPE OF PUBLICATION: Original article

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(Journal Article): Regeneration of pancreatic endocrine cells in interferon-gamma transgenic mice.
 
Sarvetnick NE, Gu D (Scripps Research Institute, Department of Neuropharmacology, La Jolla, CA.)
 
IN: Adv Exp Med Biol 1992; 321:85-89
Impact Factor(s) of Adv Exp Med Biol: 0.642 (2004)

ABSTRACT: We have shown that the pancreatic duct cells of IFN-gamma mouse are actively multiplying and that many duct cells differentiate to become endocrine cells. This islet regenerating process closely parallels the islet development during normal organogenesis in the fetus and offers a model for studying the cell lineage relationships of islet cells. The subject has received wide interest and intensive research in recent years. One of the noteworthy results of this study is the finding that duct cells retain the ability to proliferate and to differentiate into islet cells. Under normal conditions, duct cells do not continue to multiply or to differentiate. The results suggest that in the transgenic mice, the progenitor cells of embryonic multipotential duct cells transform into adult cells, but in the presence of appropriate signals or stimuli can resume their multipotential property. The appearance of hepatocytes indicates that while the cell proliferation observed largely results in endocrine cells, other differentiation pathways are occasionally possible. We also detect a few large cells containing albumin and alpha-fetoprotein in the periductal area. Pancreatic hepatocytes have also been observed in the rat after recovery from copper deficiency diet. Thus, the regeneration of islet cells in transgenic mice provides a model system for the study of factors modulating the growth pattern as well as the differentiation pathway.

TYPE OF PUBLICATION: Original article

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(Journal Article): Acid beta-galactosidase: a developmentally regulated marker of endocrine cell precursors in the human fetal pancreas.
 
Beattie GM, Levine F, Mally MI, Otonkoski T, O'Brien JS, Salomon DR, Hayek A (Lucy Thorne Whittier Children's Center, Whittier Institute for Diabetes and Endocrinology, La Jolla, California 92037, USA.)
 
IN: J Clin Endocrinol Metab 1994; 78(5):1232-1240
Impact Factor(s) of J Clin Endocrinol Metab: 5.778 (2004), 5.873 (2003), 5.16 (2001)

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ABSTRACT: Isolation of endocrine cell precursors from the human fetal pancreas will be important to the study of islet cytodifferentiation and eventually for islet transplantation in insulin-dependent diabetes. These precursor cells, from which all four islet endocrine cell types arise, are present within fetal pancreatic ductal epithelium. After enzymatic digestion and culture of the fetal pancreas, we obtained cell clusters resembling islets, but with a high content of undifferentiated cells. Histochemical staining revealed very high acid beta-galactosidase activity in over 70% of cells within the clusters. After transplantation into athymic nude mice, the islet-like cell clusters gave rise to tissue rich in differentiated endocrine cells, but low in beta-galactosidase activity. The histochemical finding of high acid beta-galactosidase activity in endocrine precursor cells was confirmed by direct measurement of lysosomal enzyme activities. In addition, we found that the expression of acid beta-galactosidase was developmentally regulated, peaking at 18-24 weeks gestation and declining to low levels in adult islets. Using a fluorogenic beta-galactosidase substrate, we were able to isolate a subpopulation of cells high in acid beta-galactosidase activity using fluorescence-activated flow cytometry. Evidence identifying these cells as potential islet cell precursors includes, besides the transplantation experiments, the colocalization in vitro of tyrosine hydroxylase, a marker of embryonic islet cells. Thus, our results indicate that high acid beta-galactosidase activity serves as a marker for a population of fetal pancreatic cells with the potential to differentiate and grow into mature pancreatic endocrine cells.

TYPE OF PUBLICATION: Original article

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(Journal Article): Presence of the endocrine cells in pancreatic ducts.
 
Bendayan M
 
IN: Pancreas 1987; 2(4):393-397
Impact Factor(s) of Pancreas: 1.872 (2004), 1.855 (2003), 1.456 (2002), 1.567 (2001)

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ABSTRACT: Pancreatic endocrine cells were found in close contact with epithelial cells (either the centro-acinar or those lining the ducts). Junctional specializations were present between both cell types, demonstrating that they are structurally associated. In some instances, the endocrine cells present in the wall of the ducts reached the luminal space having direct contact with the pancreatic juice. These cells may well be responsible for the secretion of islet hormones directly in the duct lumen. The islet hormones present in the pancreatic juice as reported previously, seems to play a significant role in the interactions between the gut and the pancreas for optimal regulation of digestive activity.

TYPE OF PUBLICATION: Review

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(Journal Article): Inducton of islet cytodifferentiation by fetal mesenchyme in adult pancreatic ductal epithelium.
 
Dudek RW, Lawrence IE, Hill RS, Johnson RC (Department of Anatomy and Cell Biology, East Carolina University, Greenville, North Carolina 27858.)
 
IN: Diabetes 1991; 40(8):1041-1048
Impact Factor(s) of Diabetes: 8.848 (2004), 8.298 (2003), 8.256 (2002), 7.7 (2001)

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ABSTRACT: Recombinant tissue consisting of adult ductal epithelium isolated from pancreas and fetal mesenchyme was transplanted subcutaneously in the inguinal region of nude mice or epididymal fat pads of rats with a tissue chamber device for short-term (8-day) or long-term (6- to 12-wk) duration. We found that recombinant tissue underwent morphogenesis and cytodifferentiation, thereby forming islets that contained cells immunocytochemically positive for insulin and glucagon. Islet cytodifferentiation occurred in approximately 20% of the recombinants. In recombinants that developed into islets, the tissue was always in close association with an extracellular matrix, nerves, and blood vessels. Controls consisting of mesenchyme alone or duct epithelium alone showed no evidence of morphogenesis of cytodifferentiation. Pancreatic rudiments were also implanted to serve as positive controls. This is the first demonstration of islet cytodifferentiation from adult duct epithelium.

TYPE OF PUBLICATION: Original article

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(Journal Article): Nestin is expressed in vascular endothelial cells in the adult human pancreas.
 
Klein T, Ling Z, Heimberg H, Madsen OD, Heller RS, Serup P (JDRF Center for Beta Cell Therapy in Europe, Department of Developmental Biology, Hagedorn Research Institute, Gentofte, Denmark., shll@hagedorn.dk )
 
IN: J Histochem Cytochem 2003; 51(6):697-706
Impact Factor(s) of J Histochem Cytochem: 2.513 (2004), 2.408 (2003), 2.718 (2001)

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ABSTRACT: In this study we examined the expression of nestin in islets, the exocrine part, and the big ducts of the adult human pancreas by immunofluorescent double staining. Two different anti-nestin antisera in combination with various pancreatic and endothelial markers were employed. Nestin-immunoreactive cells were found in islets and in the exocrine portion. All nestin-positive cells co-expressed the vascular endothelial markers PECAM-1 (CD31), endoglin (CD105), and CD34 as well as vimentin. Endocrine, acinar, and duct cells did not stain for nestin. We also demonstrated that in the area of big pancreatic ducts, nestin-positive cells represent small capillaries scattered in the connective tissue surrounding the duct epithelium and do not reside between the duct cells. We detected nestin-expressing endothelial cells located adjacent to the duct epithelium where endocrine differentiation occurs. We have shown that nestin is expressed by vascular endothelial cells in human pancreas, and therefore it is unlikely that nestin specifically marks a subpopulation of cells representing endocrine progenitors in the adult pancreas.

TYPE OF PUBLICATION: Original article

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(Journal Article): Isolation and characterization of a cell line from the epithelial cells of the human fetal pancreas.
 
Wang S, Beattie GM, Mally MI, Cirulli V, Itkin-Ansari P, Lopez AD, Hayek A, Levine F (Department of Pediatrics, UCSD School of Medicine, La Jolla, CA 92093-0634, USA.)
 
IN: Cell Transplant 1997; 6(1):59-67
Impact Factor(s) of Cell Transplant: 2.327 (2003), 2.42 (2002), 2.19 (2001)

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ABSTRACT: Pancreatic cell lines are useful for basic studies of pancreatic biology and for possible application to cell transplantation therapies for diabetes. A retroviral vector expressing simian virus 40 (SV40) T antigen and H-rasval12 was used to infect a monolayer culture of epithelial cells from an 18-wk human fetal pancreas. Infected cells gave rise to a clonal epithelial cell line, designated TRM-1. This cell line expresses epithelial markers as well as gult2 and small amounts of insulin and glucagon. TRM-1 is the first cell line to be generated from the human fetal pancreas and also the first cell line derived directly from the fetal pancreas of any species. The approach that we have used to develop TRM-1 should be applicable to isolating cell lines from other stages of human pancreatic development.

TYPE OF PUBLICATION: Original article

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