Journal articles: 'Pancreatic differentiation'

1

Mehta, Sheilendra, and George K. Gittes. "Pancreatic differentiation." Journal of Hepato-Biliary-Pancreatic Surgery 12, no. 3 (June 27, 2005): 208–17. http://dx.doi.org/10.1007/s00534-005-0981-4.

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Russ, Holger A., Limor Landsman, Christopher L. Moss, Roger Higdon, Renee L. Greer, Kelly Kaihara, Randy Salamon, Eugene Kolker, and Matthias Hebrok. "Dynamic Proteomic Analysis of Pancreatic Mesenchyme Reveals Novel Factors That Enhance Human Embryonic Stem Cell to Pancreatic Cell Differentiation." Stem Cells International 2016 (2016): 1–9. http://dx.doi.org/10.1155/2016/6183562.

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Current approaches in human embryonic stem cell (hESC) to pancreatic beta cell differentiation have largely been based on knowledge gained from developmental studies of the epithelial pancreas, while the potential roles of other supporting tissue compartments have not been fully explored. One such tissue is the pancreatic mesenchyme that supports epithelial organogenesis throughout embryogenesis. We hypothesized that detailed characterization of the pancreatic mesenchyme might result in the identification of novel factors not used in current differentiation protocols. Supplementing existing hESC differentiation conditions with such factors might create a more comprehensive simulation of normal development in cell culture. To validate our hypothesis, we took advantage of a novel transgenic mouse model to isolate the pancreatic mesenchyme at distinct embryonic and postnatal stages for subsequent proteomic analysis. Refined sample preparation and analysis conditions across four embryonic and prenatal time points resulted in the identification of 21,498 peptides with high-confidence mapping to 1,502 proteins. Expression analysis of pancreata confirmed the presence of three potentially important factors in cell differentiation: Galectin-1 (LGALS1), Neuroplastin (NPTN), and the Lamininα-2 subunit (LAMA2). Two of the three factors (LGALS1 and LAMA2) increased expression of pancreatic progenitor transcript levels in a published hESC to beta cell differentiation protocol. In addition, LAMA2 partially blocks cell culture induced beta cell dedifferentiation. Summarily, we provide evidence that proteomic analysis of supporting tissues such as the pancreatic mesenchyme allows for the identification of potentially important factors guiding hESC to pancreas differentiation.

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Pour, P. M. "Cell Differentiation during Pancreatic Carcinogenesis." Scandinavian Journal of Gastroenterology 23, sup151 (January 1988): 123–30. http://dx.doi.org/10.3109/00365528809095924.

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Mehta, Sheilendra S., and George K. Gittes. "Extracellular control of pancreatic differentiation." Seminars in Pediatric Surgery 13, no. 1 (February 2004): 25–36. http://dx.doi.org/10.1053/j.sempedsurg.2003.09.005.

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Rao, M. Sambasiva, and Janardan K. Reddy. "Pancreatic Stem Cells: Differentiation Options." Stem Cell Reviews 1, no. 3 (2005): 265–72. http://dx.doi.org/10.1385/scr:1:3:265.

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Miettinen, P. J., M. Huotari, T. Koivisto, J. Ustinov, J. Palgi, S. Rasilainen, E. Lehtonen, J. Keski-Oja, and T. Otonkoski. "Impaired migration and delayed differentiation of pancreatic islet cells in mice lacking EGF-receptors." Development 127, no. 12 (June 15, 2000): 2617–27. http://dx.doi.org/10.1242/dev.127.12.2617.

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Pancreatic acini and islets are believed to differentiate from common ductal precursors through a process requiring various growth factors. Epidermal growth factor receptor (EGF-R) is expressed throughout the developing pancreas. We have analyzed here the pancreatic phenotype of EGF-R deficient (−/−) mice, which generally die from epithelial immaturity within the first postnatal week. The pancreata appeared macroscopically normal. The most striking feature of the EGF-R (−/−) islets was that instead of forming circular clusters, the islet cells were mainly located in streak-like structures directly associated with pancreatic ducts. Based on BrdU-labelling, proliferation of the neonatal EGF-R (−/−) beta-cells was significantly reduced (2.6+/−0.4 versus 5.8+/−0.9%, P<0.01) and the difference persisted even at 7–11 days of age. Analysis of embryonic pancreata revealed impaired branching morphogenesis and delayed islet cell differentiation in the EGF-R (−/−) mice. Islet development was analyzed further in organ cultures of E12.5 pancreata. The proportion of insulin-positive cells was significantly lower in the EGF-R (−/−) explants (27+/−6 versus 48+/−8%, P<0.01), indicating delayed differentiation of the beta cells. Branching of the epithelium into ducts was also impaired. Matrix metalloproteinase (MMP-2 and MMP-9) activity was reduced 20% in EGF-R (−/−) late-gestation pancreata, as measured by gelatinase assays. Furthermore, the levels of secreted plasminogen activator inhibitor-1 (PAI-1) were markedly higher, while no apparent differences were seen in the levels of active uPA and tPa between EGF-R (−/−) and wild-type pancreata. Our findings suggest that the perturbation of EGF-R-mediated signalling can lead to a generalized proliferation defect of the pancreatic epithelia associated with a delay in beta cell development and disturbed migration of the developing islet cells as they differentiate from their precursors. Upregulated PAI-1 production and decreased gelatinolytic activity correlated to this migration defect. An intact EGF-R pathway appears to be a prerequisite for normal pancreatic development.

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Sand, J., and I. Nordback. "The Differentiation between Pancreatic Neoplastic Cysts and Pancreatic Pseudocyst." Scandinavian Journal of Surgery 94, no. 2 (June 2005): 161–64. http://dx.doi.org/10.1177/145749690509400213.

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The number of small and often asymptomatic cystic lesions detected in pancreas has increased during the last decade. Historically the vast majority of the pancreatic cystic lesions were considered pseudocysts, but in recent series the incidence of various neoplastic cysts, such as intraductal papillary mucinous neoplasm, serous cystadenomas and cystic endocrine tumours, has increased. The possible malignant potential in these cystic neoplasms warrants careful diagnostic workup to choose the optimal treatment for each patient. Patient's age, symptoms and a possible history of acute or chronic pancreatitis with known aetiology together with high quality imaging studies are important in the differential diagnosis between pseudocysts and neoplastic cysts. Endoscopic ultrasound, cyst fluid analysis and positron emission tomography may be used in selected patients, but the accuracy of these methods needs further investigation.

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Kaitsuka, Taku, Kohei Kobayashi, Wakako Otsuka, Takuya Kubo, Farzana Hakim, Fan-Yan Wei, Nobuaki Shiraki, Shoen Kume, and Kazuhito Tomizawa. "Erythropoietin facilitates definitive endodermal differentiation of mouse embryonic stem cells via activation of ERK signaling." American Journal of Physiology-Cell Physiology 312, no. 5 (May 1, 2017): C573—C582. http://dx.doi.org/10.1152/ajpcell.00071.2016.

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Artificially generated pancreatic β-cells from pluripotent stem cells are expected for cell replacement therapy for type 1 diabetes. Several strategies are adopted to direct pluripotent stem cells toward pancreatic differentiation. However, a standard differentiation method for clinical application has not been established. It is important to develop more effective and safer methods for generating pancreatic β-cells without toxic or mutagenic chemicals. In the present study, we screened several endogenous factors involved in organ development to identify the factor, which induced the efficiency of pancreatic differentiation and found that treatment with erythropoietin (EPO) facilitated the differentiation of mouse embryonic stem cells (ESCs) into definitive endoderm. At an early stage of differentiation, EPO treatment significantly increased Sox17 gene expression, as a marker of the definitive endoderm. Contrary to the canonical function of EPO, it did not affect the levels of phosphorylated JAK2 and STAT5, but stimulated the phosphorylation of ERK1/2 and Akt. The MEK inhibitor U0126 significantly inhibited EPO-induced Sox17 expression. The differentiation of ESCs into definitive endoderm is an important step for the differentiation into pancreatic and other endodermal lineages. This study suggests a possible role of EPO in embryonic endodermal development and a new agent for directing the differentiation into endodermal lineages like pancreatic β-cells.

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Tan, Mengtian, Lai Jiang, Yinglei Li, and Wei Jiang. "Dual Inhibition of BMP and WNT Signals Promotes Pancreatic Differentiation from Human Pluripotent Stem Cells." Stem Cells International 2019 (December 1, 2019): 1–15. http://dx.doi.org/10.1155/2019/5026793.

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Pathological or functional loss of pancreatic beta cells is the cause of diabetes. Understanding how signaling pathways regulate pancreatic lineage and searching for combinations of signal modulators to promote pancreatic differentiation will definitely facilitate the robust generation of functional beta cells for curing hyperglycemia. In this study, we first tested the effect of several potent BMP inhibitors on pancreatic differentiation using human embryonic stem cells. Next, we examined the endodermal lineage bias upon potent BMP inhibitor treatment and further checked the crosstalk between signal pathways governing endodermal lineage determination. Furthermore, we improved current pancreatic differentiation system based on the signaling pathway study. Finally, we used human-induced pluripotent stem cells to validate our finding. We found BMP inhibitors indeed not only blocked hepatic lineage but also impeded intestinal lineage from human definitive endoderm unexpectedly. Signaling pathway analysis indicated potent BMP inhibitor resulted in the decrease of WNT signal activity and inhibition of WNT could contribute to the improved pancreatic differentiation. Herein, we combined the dual inhibition of BMP and WNT signaling and greatly enhanced human pancreatic progenitor differentiation as well as beta cell generation from both embryonic stem cells and induced pluripotent stem cells. Conclusively, our present work identified the crosstalk between the BMP and WNT signal pathways during human endoderm patterning and pancreas specification, and provided an improved in vitro pancreatic directed differentiation protocol from human pluripotent stem cells.

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Apelqvist, Åsa, Hao Li, Lukas Sommer, Paul Beatus, David J. Anderson, Tasuku Honjo, Martin Hrabě de Angelis, Urban Lendahl, and Helena Edlund. "Notch signalling controls pancreatic cell differentiation." Nature 400, no. 6747 (August 1999): 877–81. http://dx.doi.org/10.1038/23716.

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Lee, Dong Hyeon, and Hyung Min Chung. "Differentiation into Endoderm Lineage: Pancreatic differentiation from Embryonic Stem Cells." International Journal of Stem Cells 4, no. 1 (May 30, 2011): 35–42. http://dx.doi.org/10.15283/ijsc.2011.4.1.35.

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12

Tsugata, Takako, Naruo Nikoh, Tatsuya Kin, Chika Miyagi-Shiohira, Yoshiki Nakashima, Issei Saitoh, Yasufumi Noguchi, et al. "Role of Egr1 on Pancreatic Endoderm Differentiation." Cell Medicine 10 (January 1, 2018): 215517901773317. http://dx.doi.org/10.1177/2155179017733177.

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The low efficiency of in vitro differentiation of human embryonic stem cells (hESCs) or human-induced pluripotent stem cells (iPSCs) into insulin-producing cells is a crucial hurdle for the clinical implementation of human pluripotent stem cells (PSCs). Our previous investigation into the key factors for the differentiation of PSCs into insulin-producing cells suggested that the expression of GATA binding protein 6 (GATA6) and Gremlin 1 (GREM1) and inhibition of early growth response protein 1 (Egr1) may be important factors. In this study, we investigated the role of Egr1 in pancreas development. The transfection of small interfering RNA (siRNA) of Egr1 in the early phase induced the differentiation of iPSCs derived from fibroblasts (FiPSCs) into pancreatic endoderm and insulin-producing cells. In contrast, the downregulation of Egr1 in the late phase suppressed the differentiation of FiPSCs into pancreatic endoderm and insulin-producing cells. In addition, the overexpression of Egr1 suppressed the differentiation of iPSCs derived from pancreatic cells into pancreatic endoderm and insulin-producing cells. These data suggest that the downregulation of Egr1 in the early phase can efficiently induce the differentiation of iPSCs into insulin-producing cells.

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13

Milanesi, Anna, Jang-Won Lee, Qijin Xu, Laura Perin, and John S. Yu. "Differentiation of nestin-positive cells derived from bone marrow into pancreatic endocrine and ductal cells in vitro." Journal of Endocrinology 209, no. 2 (February 17, 2011): 193–201. http://dx.doi.org/10.1530/joe-10-0344.

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Promising results of pancreatic islet transplantation to treat type 1 diabetes mellitus, combined with severe shortage of donor pancreata, have spurred efforts to generate pancreatic islet-like cells and insulin-producing β-cells from various progenitor populations. In this study, we show for the first time that multipotent nestin-positive stem cells selected from rat bone marrow can be differentiated into pancreatic ductal and insulin-producing β-cells in vitro. We report an effective multistep protocol in a serum-free system, which could efficiently induce β-cell differentiation from multipotent nestin-positive bone marrow stem cells. To enhance the induction and differentiation toward pancreatic lineage we used trichostatin A, an important regulator of chromatin remodeling, and 5-aza 2′ deoxycytidine, an inhibitor of DNA methylase. All-trans retinoic acid was then utilized to promote pancreatic differentiation. We sequentially induced important transcription factor genes, such as Pdx1, Ngn3, and Pax6, following the in vivo development timeline of the pancreas in rats. Furthermore, in the final stage with the presence of nicotinamide, the induced cells expressed islet and ductal specific markers. The differentiated cells not only expressed insulin and glucose transporter 2, but also displayed a glucose-responsive secretion of the hormone. Our results delineate a new model system to study islet neogenesis and possible pharmaceutical targets. Nestin-positive bone marrow stem cells may be therapeutically relevant for β-cell replacement in type 1 diabetes.

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14

SKOUDY, Anouchka, Meritxell ROVIRA, Pierre SAVATIER, Franz MARTIN, Trinidad LEÓN-QUINTO, Bernat SORIA, and Francisco X. REAL. "Transforming growth factor (TGF)beta, fibroblast growth factor (FGF) and retinoid signalling pathways promote pancreatic exocrine gene expression in mouse embryonic stem cells." Biochemical Journal 379, no. 3 (May 1, 2004): 749–56. http://dx.doi.org/10.1042/bj20031784.

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Extracellular signalling cues play a major role in the activation of differentiation programmes. Mouse embryonic stem (ES) cells are pluripotent and can differentiate into a wide variety of specialized cells. Recently, protocols designed to induce endocrine pancreatic differentiation in vitro have been designed but little information is currently available concerning the potential of ES cells to differentiate into acinar pancreatic cells. By using conditioned media of cultured foetal pancreatic rudiments, we demonstrate that ES cells can respond in vitro to signalling pathways involved in exocrine development and differentiation. In particular, modulation of the hedgehog, transforming growth factor β, retinoid, and fibroblast growth factor pathways in ES cell-derived embryoid bodies (EB) resulted in increased levels of transcripts encoding pancreatic transcription factors and cytodifferentiation markers, as demonstrated by RT-PCR. In EB undergoing spontaneous differentiation, expression of the majority of the acinar genes (i.e. amylase, carboxypeptidase A and elastase) was induced after the expression of endocrine genes, as occurs in vivo during development. These data indicate that ES cells can undergo exocrine pancreatic differentiation with a kinetic pattern of expression reminiscent of pancreas development in vivo and that ES cells can be coaxed to express an acinar phenotype by activation of signalling pathways known to play a role in pancreatic development and differentiation.

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Chen, Wei, Salma Begum, Lynn Opare-Addo, Justin Garyu, Thomas F. Gibson, Alfred L. M. Bothwell, Virginia E. Papaioannou, and Kevan C. Herold. "Promotion of β-Cell Differentiation in Pancreatic Precursor Cells by Adult Islet Cells." Endocrinology 150, no. 2 (February 1, 2009): 570–79. http://dx.doi.org/10.1210/en.2008-1009.

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It is thought that differentiation of β-cell precursors into mature cells is largely autonomous, but under certain conditions differentiation can be modified by external factors. The factors that modify β-cell differentiation have not been identified. In this study, we tested whether adult islet cells can affect the differentiation process in mouse and human pancreatic anlage cells. We assessed β-cell proliferation and differentiation in mouse and human pancreatic anlage cells cocultured with adult islet cells or βTC3 cells using cellular, molecular, and immunohistochemical methods. Differentiation of murine anlage cells into β-cells was induced by mature islet cells. It was specific for β-cells and not a general feature of endodermal derived cells. β-Cell differentiation required cell-cell contact. The induced cells acquired features of mature β-cells including increased expression of β-cell transcription factors and surface expression of receptor for stromal cell-derived factor 1 and glucose transporter-2 (GLUT-2). They secreted insulin in response to glucose and could correct hyperglycemia in vivo when cotransplanted with vascular cells. Human pancreatic anlage cells responded in a similar manner and showed increased expression of pancreatic duodenal homeobox 1 and v-maf musculoaponeurotic fibrosarcoma oncogene homolog A and increased production of proinsulin when cocultured with adult islets. We conclude that mature β-cells can modify the differentiation of precursor cells and suggest a mechanism whereby changes in differentiation of β-cells can be affected by other β-cells. Mature β cells affect differentiation of pancreatic anlage cells into functional β cells. The differentiated cells respond to glucose and ameliorate diabetes.

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Dettmer, Rabea, Karsten Cirksena, Julia Münchhoff, Jasmin Kresse, Ulf Diekmann, Isabell Niwolik, Falk F. R. Buettner, and Ortwin Naujok. "FGF2 Inhibits Early Pancreatic Lineage Specification during Differentiation of Human Embryonic Stem Cells." Cells 9, no. 9 (August 20, 2020): 1927. http://dx.doi.org/10.3390/cells9091927.

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Growth factors are important regulators during organ development. For many vertebrates (but not humans) it is known how they contribute to the formation and expansion of PDX1-positive cells during pancreas organogenesis. Here, the effects of the fibroblast growth factors FGF2, FGF7, FGF10, and epidermal growth factor (EGF) on pancreas development in humans were assessed by using human pluripotent stem cells (hPSCs). During this, FGF2 was identified as a potent anti-pancreatic factor whereas FGF7, FGF10, and EGF increased the cell mass while retaining PDX1-positivity. FGF2 increased the expression of the anti-pancreatic factor sonic hedgehog (SHH) while suppressing PDX1 in a dose-dependent manner. Differentiating cells secreted SHH to the medium and we interrogated the cells’ secretome during differentiation to globally examine the composition of secreted signaling factors. Members of the TGF-beta-, Wnt-, and FGF-pathways were detected. FGF17 showed a suppressive anti-pancreatic effect comparable to FGF2. By inhibition of specific branches of FGF-receptor signaling, we allocated the SHH-induction by FGF2 to MEK/ERK-signaling and the anti-pancreatic effect of FGF2 to the receptor variant FGFR1c or 3c. Altogether, we report findings on the paracrine activity of differentiating hPSCs during generation of pancreatic progenitors. These observations suggest a different role for FGF2 in humans compared to animal models of pancreas organogenesis.

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Cirulli, V., L. Crisa, G. M. Beattie, M. I. Mally, A. D. Lopez, A. Fannon, A. Ptasznik, et al. "KSA Antigen Ep-CAM Mediates Cell–Cell Adhesion of Pancreatic Epithelial Cells: Morphoregulatory Roles in Pancreatic Islet Development." Journal of Cell Biology 140, no. 6 (March 23, 1998): 1519–34. http://dx.doi.org/10.1083/jcb.140.6.1519.

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Cell adhesion molecules (CAMs) are important mediators of cell–cell interactions and regulate cell fate determination by influencing growth, differentiation, and organization within tissues. The human pancarcinoma antigen KSA is a glycoprotein of 40 kD originally identified as a marker of rapidly proliferating tumors of epithelial origin. Interestingly, most normal epithelia also express this antigen, although at lower levels, suggesting that a dynamic regulation of KSA may occur during cell growth and differentiation. Recently, evidence has been provided that this glycoprotein may function as an epithelial cell adhesion molecule (Ep-CAM). Here, we report that Ep-CAM exhibits the features of a morphoregulatory molecule involved in the development of human pancreatic islets. We demonstrate that Ep-CAM expression is targeted to the lateral domain of epithelial cells of the human fetal pancreas, and that it mediates calcium-independent cell–cell adhesion. Quantitative confocal immunofluorescence in fetal pancreata identified the highest levels of Ep-CAM expression in developing islet-like cell clusters budding from the ductal epithelium, a cell compartment thought to comprise endocrine progenitors. A surprisingly reversed pattern was observed in the human adult pancreas, displaying low levels of Ep-CAM in islet cells and high levels in ducts. We further demonstrate that culture conditions promoting epithelial cell growth induce upregulation of Ep-CAM, whereas endocrine differentiation of fetal pancreatic epithelial cells, transplanted in nude mice, is associated with a downregulation of Ep-CAM expression. In addition, a blockade of Ep-CAM function by KS1/4 mAb induced insulin and glucagon gene transcription and translation in fetal pancreatic cell clusters. These results indicate that developmentally regulated expression and function of Ep-CAM play a morphoregulatory role in pancreatic islet ontogeny.

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18

Holt, Chuck. "Differentiation & Risk Stratification of Pancreatic Cysts." Oncology Times 42, no. 4 (February 2020): 1. http://dx.doi.org/10.1097/01.cot.0000655936.04726.c0.

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19

Guthrie, Janice, John A. Williams, and Craig D. Logsdon. "Growth and Differentiation of Pancreatic Acinar Cells." Pancreas 6, no. 5 (September 1991): 506–13. http://dx.doi.org/10.1097/00006676-199109000-00002.

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20

Soria, Bernat. "In-vitro differentiation of pancreatic β-cells." Differentiation 68, no. 4-5 (October 2001): 205–19. http://dx.doi.org/10.1046/j.1432-0436.2001.680408.x.

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21

Seimiya, Takahiro, Motoyuki Otsuka, Takuma Iwata, Eri Tanaka, Tatsunori Suzuki, Kazuma Sekiba, Mari Yamagami, Rei Ishibashi, and Kazuhiko Koike. "Inflammation and de-differentiation in pancreatic carcinogenesis." World Journal of Clinical Cases 6, no. 15 (December 6, 2018): 882–91. http://dx.doi.org/10.12998/wjcc.v6.i15.882.

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22

Foster, Jayne L., Georgia Williams, Lindy J. Williams, and Bernard E. Tuch. "Differentiation of Transplanted Microencapsulated Fetal Pancreatic Cells." Transplantation 83, no. 11 (June 2007): 1440–48. http://dx.doi.org/10.1097/01.tp.0000264555.46417.7d.

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Blyszczuk, Przemyslaw, and Anna M. Wobus. "Stem cells and pancreatic differentiation in vitro." Journal of Biotechnology 113, no. 1-3 (September 2004): 3–13. http://dx.doi.org/10.1016/j.jbiotec.2004.03.023.

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Hembree, Mark, Kok-Hooi Yew, Krishna Prasadan, Barry Preuett, Christina Cantu, Christopher McFall, Amanda Crowley, Susan Sharp, Charles Snyder, and George Gittes. "TGF-beta signaling in pancreatic cell differentiation." Journal of the American College of Surgeons 199, no. 3 (September 2004): 85. http://dx.doi.org/10.1016/j.jamcollsurg.2004.05.183.

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Edlund, H. "Factors controlling pancreatic cell differentiation and function." Diabetologia 44, no. 9 (September 1, 2001): 1071–79. http://dx.doi.org/10.1007/s001250100623.

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Leach, Steven D. "Epithelial Differentiation in Pancreatic Development and Neoplasia." Journal of Clinical Gastroenterology 39, Supplement 2 (April 2005): S78—S82. http://dx.doi.org/10.1097/01.mcg.0000155547.83901.a3.

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Humphrey, Rohan K., Murray S. Smith, Bernard E. Tuch, and Alberto Hayek. "Regulation of pancreatic cell differentiation and morphogenesis." Pediatric Diabetes 3, no. 1 (March 2002): 46–63. http://dx.doi.org/10.1034/j.1399-5448.2002.30109.x.

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Li, Z., S. S. Mehta, K. Prasadan, M. Hembree, G. W. Holcomb, D. J. Ostlie, C. L. Snyder, and G. K. Gittes. "Pleiotrophin signaling in pancreatic organogenesis and differentiation." Journal of Surgical Research 114, no. 2 (October 2003): 283–84. http://dx.doi.org/10.1016/j.jss.2003.08.043.

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Wang, Xiuli, and Kaiming Ye. "Directed pancreatic differentiation from embryonic stem cells." Journal of Biotechnology 136 (October 2008): S127. http://dx.doi.org/10.1016/j.jbiotec.2008.07.267.

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Dadheech, Nidheesh, Sanket Soni, Abhay Srivastava, Sucheta Dadheech, Shivika Gupta, Renjitha Gopurappilly, Ramesh R. Bhonde, and Sarita Gupta. "A Small Molecule Swertisin fromEnicostemma littoraleDifferentiates NIH3T3 Cells into Islet-Like Clusters and Restores Normoglycemia upon Transplantation in Diabetic Balb/c Mice." Evidence-Based Complementary and Alternative Medicine 2013 (2013): 1–20. http://dx.doi.org/10.1155/2013/280392.

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Aim. Stem cell therapy is one of the upcoming therapies for the treatment of diabetes. Discovery of potent differentiating agents is a prerequisite for increasing islet mass. The present study is an attempt to screen the potential of novel small biomolecules for their differentiating property into pancreatic islet cells using NIH3T3, as representative of extra pancreatic stem cells/progenitors.Methods. To identify new agents that stimulate islet differentiation, we screened various compounds isolated fromEnicostemma littoraleusing NIH3T3 cells and morphological changes were observed. Characterization was performed by semiquantitative RT-PCR, Q-PCR, immunocytochemistry, immunoblotting, and insulin secretion assay for functional response in newly generated islet-like cell clusters (ILCC). Reversal of hyperglycemia was monitored after transplanting ILCC in STZ-induced diabetic mice.Results. Among various compounds tested, swertisin, an isolated flavonoid, was the most effective in differentiating NIH3T3 into endocrine cells. Swertisin efficiently changed the morphology of NIH3T3 cells from fibroblastic to round aggregate cell cluster in huge numbers. Dithizone (DTZ) stain primarily confirmed differentiation and gene expression studies signified rapid onset of differentiation signaling cascade in swertisin-induced ILCC. Molecular imaging and immunoblotting further confirmed presence of islet specific proteins. Moreover, glucose induced insulin release (in vitro) and decreased fasting blood glucose (FBG) (in vivo) in transplanted diabetic BALB/c mice depicted functional maturity of ILCC. Insulin and glucagon expression in excised islet grafts illustrated survival and functional integrity.Conclusions. Rapid induction for islet differentiation by swertisin, a novel herbal biomolecule, provides low cost and readily available differentiating agent that can be translated as a therapeutic tool for effective treatment in diabetes.

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Lilly, Anna C., Aizhan Surumbayeva, Theodore Nguyen, Igor Astsaturov, and Erica A. Golemis. "Abstract 2178: Diet-modulated SCAP-SREBP signaling is essential for acinar cell differentiation, pancreatic morphogenesis, and pancreatic adiposity." Cancer Research 82, no. 12_Supplement (June 15, 2022): 2178. http://dx.doi.org/10.1158/1538-7445.am2022-2178.

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Abstract High levels of dietary fats are associated with pancreatitis, diabetes, and pancreatic cancer. Sterol regulatory element binding protein Cleavage-Activating Protein (SCAP) is an essential intermediate in lipid-regulated activation of Sterol Regulatory Element Binding Protein (SREBP) transcription factors, which induce expression of genes regulating lipid homeostasis. We previously demonstrated that the elevated SREBP1 arising from inhibition of the cholesterol biosynthetic pathway in mice genetically predisposed to pancreatic cancer additionally transcribed genes that induced epithelial-mesenchymal transition, promoting basal rather than glandular cancer. To further evaluate SCAP and SREBP function in the pancreas, we developed a new mouse model with selective pancreatic knockout of the Scapf/f gene under the control of the Pdx1-Cre promoter (ScapΔpanc mice). Although size of the pancreas in ScapΔpanc neonates was unaffected, and number of islets was normal, there was a reduced number of acinar cells, and some evidence of disorganized tissue structure. Preliminary histopatholgical assessment of pancreatic tissue of ScapΔpanc neonates indicated no acinar cell apoptosis, and unimpaired acinar proliferation, suggesting loss of Scap may cause a differentiation defect. Further supporting this idea, siRNA depletion of Scap in the rat AR42J acinar cell line resulted in loss of markers of mature acinar cell identity. ScapΔpanc pancreata underwent progressive and selective loss of acinar cells as mice aged, with three-month old mice having large areas of acinar cell loss, and mislocalization of ductal cells. Coupled with this loss was a large increase in pancreatic adipocytes and mesenchymal cells, resulting in a highly disorganized tissue morphology accompanied by signs of inflammation. These phenotypes were exacerbated in mice maintained on high fat or high carbohydrate diet. Together, these results imply that SCAP and SREBP signaling in the pancreas plays an important role in mediating dietary modulation of pancreatic development, acinar cell homeostasis, and restraint of pancreatic adiposity. Intrapancreatic fat, associated with obesity and chronic pancreatitis, is a known risk factor for pancreatic cancer, and SCAP polymorphisms have been to interact with diet in regulating obesity and blood pressure in humans; we propose SCAP-SREBP signaling in the pancreas may mediate dietary promotion of pancreatic cancer risk. Citation Format: Anna C. Lilly, Aizhan Surumbayeva, Theodore Nguyen, Igor Astsaturov, Erica A. Golemis. Diet-modulated SCAP-SREBP signaling is essential for acinar cell differentiation, pancreatic morphogenesis, and pancreatic adiposity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2178.

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Dubey, A., H. N. Malik, D. K. Singhal, S. Saugandhika, S. Boateng, R. Singhal, S. Fatima, et al. "198 ISOLATION, CHARACTERIZATION, AND IN VITRO DIFFERENTIATION OF GOAT ADIPOSE-TISSUE-DERIVED MESENCHYMAL STEM CELLS INTO PANCREATIC ISLETS-LIKE CELLS." Reproduction, Fertility and Development 26, no. 1 (2014): 213. http://dx.doi.org/10.1071/rdv26n1ab198.

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The present study was carried out for isolation of goat (Capra hircus) adipose-tissue-derived stem cells (gADSCs) from adipose tissue, their characterization, and in vitro differentiation of gADSCs into pancreatic islets-like cells by giving conditioned medium. Goat ADSCs were isolated from goat adipose tissue by the enzymatic digestion method and were enriched by filtering through a 41-μm filter. Thus, filtered cells resuspended in a cell culture flask containing growth enriching medium and cultured in 5% CO2 in air at 38.5°C. Goat ADSCs were characterised by amplification of mesenchymal stem cell specific markers i.e. CD29, CD34, CD44, CD90, and CD166 as positive markers and CD41 and CD71 as negative markers. Immunocytochemistry of mesenchymal stem cell was also carried out with specific markers CD44 and CD90. Goat ADSCs were further characterised by in vitro differentiating them into osteocytes, chondrocytes, and adipocytes. For in vitro differentiation of gADSCs into osteocytes gADSCs were supplemented with conditioned medium i.e. DMEM containing fetal bovine serum (FBS), dexamethazone, B-glycerol phosphate and L-ascorbic acid. Osteogenic differentiation was confirmed by positive Alizarin red S staining and amplification of Osteopontin and Collagen I genes. For differentiation into chondrocytes cells, gADSCs were incubated in DMEM/F12 containing dexamethazone, ITX, BMP-4, and FBS for 21 days. Differentiated cells were confirmed by positive Safranin O staining and expression of chondrocytes specific Collagen III and Aggrecan genes. For adipogenesis, gADSCs were incubated with DMEM/F12 containing FBS, dexamethasone, and ITX and differentiated cells were confirmed by positive Oil Red O staining and amplification of adipocytes specific genes i.e. LPL, PPRγ and PPRα. For in-vitro differentiation gADSCs into pancreatic islets-like cells on the third or fourth passage gADSCs were incubated in conditioned medium containing serum-free DMEM/F12 medium with glucose (17.5 mM) in the presence of nicotinamide (10 mM), activin-A (2 nM), exendin-4 (10 nM), pentagastrin (10 nM), retinoic acid (10 μM) and mercaptoethanol (20 μM). The in vitro differentiation gADSCs into pancreatic islets-like cells was confirmed by amplification of pancreatic endoderm specific genes i.e. igf-1, sst, ngn3, pdx-1, isl-1, c-kit, thy-1, and Glut-2, and no expression was detected for above endoderm specific genes in undifferentiated gADSCs. Pancreatic islets-like cells were further characterised by immunostaining and Western blotting of Pdx-1, insulin, and Islets-1 specific protein. It could be concluded that gADSCs was differentiated into different lineages and secretory insulin was produced from pancreatic islets-like cells.

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Artioukh, Dmitri Y., and Michael R. Zeiderman. "Diagnostic difficulties in the differentiation of pancreatic pseudocyst and cystic pancreatic neoplasm." Annals of the College of Surgeons Hong Kong 6, no. 4 (November 2002): 121–22. http://dx.doi.org/10.1046/j.1442-2034.2002.00143.x.

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Piper, K., S. Brickwood, LW Turnpenny, IT Cameron, SG Ball, DI Wilson, and NA Hanley. "Beta cell differentiation during early human pancreas development." Journal of Endocrinology 181, no. 1 (April 1, 2004): 11–23. http://dx.doi.org/10.1677/joe.0.1810011.

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Understanding gene expression profiles during early human pancreas development is limited by comparison to studies in rodents. In this study, from the inception of pancreatic formation, embryonic pancreatic epithelial cells, approximately half of which were proliferative, expressed nuclear PDX1 and cytoplasmic CK19. Later, in the fetal pancreas, insulin was the most abundant hormone detected during the first trimester in largely non-proliferative cells. At sequential stages of early fetal development, as the number of insulin-positive cell clusters increased, the detection of CK19 in these cells diminished. PDX1 remained expressed in fetal beta cells. Vascular structures were present within the loose stroma surrounding pancreatic epithelial cells during embryogenesis. At 10 weeks post-conception (w.p.c.), all clusters containing more than ten insulin-positive cells had developed an intimate relationship with these vessels, compared with the remainder of the developing pancreas. At 12-13 w.p.c., human fetal islets, penetrated by vasculature, contained cells independently immunoreactive for insulin, glucagon, somatostatin and pancreatic polypeptide (PP), coincident with the expression of maturity markers prohormone convertase 1/3 (PC1/3), islet amyloid polypeptide, Chromogranin A and, more weakly, GLUT2. These data support the function of fetal beta cells as true endocrine cells by the end of the first trimester of human pregnancy.

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Krüger, Jana, Markus Breunig, Lino Pascal Pasquini, Mareen Morawe, Alexander Groß, Frank Arnold, Ronan Russell, et al. "Functional Genomic Screening in Human Pluripotent Stem Cells Reveals New Roadblocks in Early Pancreatic Endoderm Formation." Cells 11, no. 3 (February 8, 2022): 582. http://dx.doi.org/10.3390/cells11030582.

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Human pluripotent stem cells, with their ability to proliferate indefinitely and to differentiate into virtually all cell types of the human body, provide a novel resource to study human development and to implement relevant disease models. Here, we employed a human pancreatic differentiation platform complemented with an shRNA screen in human pluripotent stem cells (PSCs) to identify potential drivers of early endoderm and pancreatic development. Deep sequencing followed by abundancy ranking pinpointed six top hit genes potentially associated with either improved or impaired endodermal differentiation, which were selected for functional validation in CRISPR-Cas9 mediated knockout (KO) lines. Upon endoderm differentiation (DE), particularly the loss of SLC22A1 and DSC2 led to impaired differentiation efficiency into CXCR4/KIT-positive DE cells. qPCR analysis also revealed changes in differentiation markers CXCR4, FOXA2, SOX17, and GATA6. Further differentiation of PSCs to the pancreatic progenitor (PP) stage resulted in a decreased proportion of PDX1/NKX6-1-positive cells in SLC22A1 KO lines, and in DSC2 KO lines when differentiated under specific culture conditions. Taken together, our study reveals novel genes with potential roles in early endodermal development.

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Nair, Gopika G., and Jon S. Odorico. "PTF1a Activity in Enriched Posterior Foregut Endoderm, but Not Definitive Endoderm, Leads to Enhanced Pancreatic Differentiation in anIn VitroMouse ESC-Based Model." Stem Cells International 2016 (2016): 1–15. http://dx.doi.org/10.1155/2016/6939438.

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Transcription factors are tools repetitively used by the embryo to generate a variety of lineages. Hence, their context of activation is an important determinant of their ability to specifically trigger certain cell fates, but not others. The context is also consequential when considering directing differentiation of embryonic stem cells (ESCs). In this study, we sought to assess the context of pancreatic transcription factor 1a (PTF1a) activation in reference to its propancreatic effects in mouse ESCs (mESCs). We hypothesized that an enriched endodermal population would respond to PTF1a and trigger the pancreatic program more effectively than a spontaneously differentiated population. Using anin vitromodel of pancreas development that we recently established, we found that inducing PTF1a in highly enriched definitive endoderm did not promote pancreatic differentiation but induction in more differentiated endoderm, specifically posterior foregut endoderm, did form pancreatic progenitors. These progenitors never underwent terminal differentiation to endocrine or acinar phenotype. However, a short 3D culture period, prior to PTF1a induction, led to the generation of monohormonal insulin+cells and amylase-expressing cells. Our findings suggest that enriched posterior foregut endoderm is competent to respond to PTF1a’s propancreatic activity; but a 3D culture environment is essential for terminal differentiation of pancreatic progenitors.

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Yabe, Shigeharu G., Satsuki Fukuda, Junko Nishida, Fujie Takeda, Kiyoko Nashiro, and Hitoshi Okochi. "Efficient induction of pancreatic alpha cells from human induced pluripotent stem cells by controlling the timing for BMP antagonism and activation of retinoic acid signaling." PLOS ONE 16, no. 1 (January 11, 2021): e0245204. http://dx.doi.org/10.1371/journal.pone.0245204.

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Diabetes mellitus is caused by breakdown of blood glucose homeostasis, which is maintained by an exquisite balance between insulin and glucagon produced respectively by pancreatic beta cells and alpha cells. However, little is known about the mechanism of inducing glucagon secretion from human alpha cells. Many methods for generating pancreatic beta cells from human pluripotent stem cells (hPSCs) have been reported, but only two papers have reported generation of pancreatic alpha cells from hPSCs. Because NKX6.1 has been suggested as a very important gene for determining cell fate between pancreatic beta and alpha cells, we searched for the factors affecting expression of NKX6.1 in our beta cell differentiation protocols. We found that BMP antagonism and activation of retinoic acid signaling at stage 2 (from definitive endoderm to primitive gut tube) effectively suppressed NKX6.1 expression at later stages. Using two different hPSCs lines, treatment with BMP signaling inhibitor (LDN193189) and retinoic acid agonist (EC23) at Stage 2 reduced NKX6.1 expression and allowed differentiation of almost all cells into pancreatic alpha cells in vivo after transplantation under a kidney capsule. Our study demonstrated that the cell fate of pancreatic cells can be controlled by adjusting the expression level of NKX6.1 with proper timing of BMP antagonism and activation of retinoic acid signaling during the pancreatic differentiation process. Our method is useful for efficient induction of pancreatic alpha cells from hPSCs.

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Ullah, Imran, Ran Lee, Keon Bong Oh, Seongsoo Hwang, Youngim Kim, Tai-Young Hur, and Sun A. Ock. "Transdifferentiation of α-1,3-galactosyltransferase knockout pig bone marrow derived mesenchymal stem cells into pancreatic β-like cells by microenvironment modulation." Asian-Australasian Journal of Animal Sciences 33, no. 11 (November 1, 2020): 1837–47. http://dx.doi.org/10.5713/ajas.19.0796.

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Objective: To evaluate the pancreatic differentiation potential of α-1,3-galactosyltransferase knockout (GalTKO) pig-derived bone marrow-derived mesenchymal stem cells (BM-MSCs) using epigenetic modifiers with different pancreatic induction media.Methods: The BM-MSCs have been differentiated into pancreatic β-like cells by inducing the overexpression of key transcription regulatory factors or by exposure to specific soluble inducers/small molecules. In this study, we evaluated the pancreatic differentiation of GalTKO pig-derived BM-MSCs using epigenetic modifiers, 5-azacytidine (5-Aza) and valproic acid (VPA), and two types of pancreatic induction media – advanced Dulbecco's modified Eagle's medium (ADMEM)-based and N2B27-based media. GalTKO BM-MSCs were treated with pancreatic induction media and the expression of pancreas-islets-specific markers was evaluated by real-time quantitative polymerase chain reaction, Western blotting, and immunofluorescence. Morphological changes and changes in the 5'-C-phosphate-G-3' (CpG) island methylation patterns were also evaluated.Results: The expression of the pluripotent marker (POU class 5 homeobox 1 [OCT4]) was upregulated upon exposure to 5-Aza and/or VPA. GalTKO BM-MSCs showed increased expression of neurogenic differentiation 1 in the ADMEM-based (5-Aza) media, while the expression of NK6 homeobox 1 was elevated in cells induced with the N2B27-based (5-Aza) media. Moreover, the morphological transition and formation of islets-like cellular clusters were also prominent in the cells induced with the N2B27-based media with 5-Aza. The higher insulin expression revealed the augmented trans-differentiation ability of GalTKO BM-MSCs into pancreatic β-like cells in the N2B27-based media than in the ADMEM-based media.Conclusion: 5-Aza treated GalTKO BM-MSCs showed an enhanced demethylation pattern in the second CpG island of the OCT4 promoter region compared to that in the GalTKO BM-MSCs. The exposure of GalTKO pig-derived BM-MSCs to the N2B27-based microenvironment can significantly enhance their trans-differentiation ability into pancreatic β-like cells.

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Ishii, Yasutaka, Masahiro Serikawa, Tomofumi Tsuboi, Ryota Kawamura, Ken Tsushima, Shinya Nakamura, Tetsuro Hirano, et al. "Role of Endoscopic Ultrasonography and Endoscopic Retrograde Cholangiopancreatography in the Diagnosis of Pancreatic Cancer." Diagnostics 11, no. 2 (February 4, 2021): 238. http://dx.doi.org/10.3390/diagnostics11020238.

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Pancreatic cancer has the poorest prognosis among all cancers, and early diagnosis is essential for improving the prognosis. Along with radiologic modalities, such as computed tomography (CT) and magnetic resonance imaging (MRI), endoscopic modalities play an important role in the diagnosis of pancreatic cancer. This review evaluates the roles of two of those modalities, endoscopic ultrasonography (EUS) and endoscopic retrograde cholangiopancreatography (ERCP), in the diagnosis of pancreatic cancer. EUS can detect pancreatic cancer with higher sensitivity and has excellent sensitivity for the diagnosis of small pancreatic cancer that cannot be detected by other imaging modalities. EUS may be useful for the surveillance of pancreatic cancer in high-risk individuals. Contrast-enhanced EUS and EUS elastography are also useful for differentiating solid pancreatic tumors. In addition, EUS-guided fine needle aspiration shows excellent sensitivity and specificity, even for small pancreatic cancer, and is an essential examination method for the definitive pathological diagnosis and treatment decision strategy. On the other hand, ERCP is invasive and performed less frequently for the purpose of diagnosing pancreatic cancer. However, ERCP is essential in cases that require evaluation of pancreatic duct stricture that may be early pancreatic cancer or those that require differentiation from focal autoimmune pancreatitis.

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Hohwieler, Meike, Martin Müller, Pierre-Olivier Frappart, and Sandra Heller. "Pancreatic Progenitors and Organoids as a Prerequisite to Model Pancreatic Diseases and Cancer." Stem Cells International 2019 (February 25, 2019): 1–11. http://dx.doi.org/10.1155/2019/9301382.

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Embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) are characterized by their unique capacity to stepwise differentiate towards any particular cell type in an adult organism. Pluripotent stem cells provide a beneficial platform to model hereditary diseases and even cancer development. While the incidence of pancreatic diseases such as diabetes and pancreatitis is increasing, the understanding of the underlying pathogenesis of particular diseases remains limited. Only a few recent publications have contributed to the characterization of human pancreatic development in the fetal stage. Hence, most knowledge of pancreatic specification is based on murine embryology. Optimizing and understanding current in vitro protocols for pancreatic differentiation of ESCs and iPSCs constitutes a prerequisite to generate functional pancreatic cells for better disease modeling and drug discovery. Moreover, human pancreatic organoids derived from pluripotent stem cells, organ-restricted stem cells, and tumor samples provide a powerful technology to model carcinogenesis and hereditary diseases independent of genetically engineered mouse models. Herein, we summarize recent advances in directed differentiation of pancreatic organoids comprising endocrine cell types. Beyond that, we illustrate up-and-coming applications for organoid-based platforms.

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Kim, Hyo-Sup, Seung-Hyun Hong, Seung-Hoon Oh, Jae-Hyeon Kim, Myung-Shik Lee, and Moon-Kyu Lee. "Activin A, exendin-4, and glucose stimulate differentiation of human pancreatic ductal cells." Journal of Endocrinology 217, no. 3 (March 15, 2013): 241–52. http://dx.doi.org/10.1530/joe-12-0474.

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Islet transplantation is one treatment option for diabetes mellitus. However, novel sources of pancreatic islets or insulin-producing cells are required because the amount of donor tissue available is severely limited. Pancreatic ductal cells are an alternative source of β-cells because they have the potential to differentiate into insulin-producing cells. We investigated whether treatment of human pancreatic ductal cells with activin A (ActA) and exendin-4 (EX-4) stimulated transdifferentiation of the cells, bothin vitroandin vivo. We treated human pancreatic ductal cells with ActA and EX-4 in high-glucose media to induce differentiation into insulin-producing cells and transplanted the cells into streptozotocin-induced diabetic nude mice. Co-treatment of mice with ActA and EX-4 promoted cell proliferation, induced expression of pancreatic β-cell-specific markers, and caused glucose-induced insulin secretion compared with the ActA or EX-4 mono-treatment groups respectively. When pancreatic ductal cells treated with ActA and EX-4 in high-glucose media were transplanted into diabetic nude mice, their blood glucose levels normalized and insulin was detected in the graft. These findings suggest that pancreatic ductal cells have a potential to replace pancreatic islets for the treatment of diabetes mellitus when the ductal cells are co-treated with ActA, EX-4, and glucose to promote their differentiation into functional insulin-producing cells.

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Zhou, Ziyu, Xiaojie Ma, and Saiyong Zhu. "Recent advances and potential applications of human pluripotent stem cell-derived pancreatic β cells." Acta Biochimica et Biophysica Sinica 52, no. 7 (May 23, 2020): 708–15. http://dx.doi.org/10.1093/abbs/gmaa047.

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Abstract Diabetes mellitus is characterized by chronic high blood glucose levels resulted from deficiency and/or dysfunction of insulin-producing pancreatic β cells. Generation of large amounts of functional pancreatic β cells is critical for the study of pancreatic biology and treatment of diabetes. Recent advances in directed differentiation of pancreatic β-like cells from human pluripotent stem cells (hPSCs) can provide patient-specific and disease-relevant target cells. With the improved differentiation protocols, it is now possible to generate large amounts of functional human pancreatic β-like cells that can response to high level of glucose both in vitro and in vivo. Combined with precise genomic editing, biomedical engineering, high throughput profiling, bioinformatics, and high throughput genetic and chemical screening, these hPSC-derived pancreatic β-like cells will hold great potentials in disease modeling, drug discovery, and cell-based therapies. In this review, we summarize the recent progress in human pancreatic β-like cells derived from hPSCs and discuss their potential applications.

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Chen, Andy Chun Hang, Wen Huang, Sze Wan Fong, Chris Chan, Kai Chuen Lee, William Shu Biu Yeung, and Yin Lau Lee. "Hyperglycemia Altered DNA Methylation Status and Impaired Pancreatic Differentiation from Embryonic Stem Cells." International Journal of Molecular Sciences 22, no. 19 (October 3, 2021): 10729. http://dx.doi.org/10.3390/ijms221910729.

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The prevalence of type 2 diabetes (T2D) is rapidly increasing across the globe. Fetal exposure to maternal diabetes was correlated with higher prevalence of impaired glucose tolerance and T2D later in life. Previous studies showed aberrant DNA methylation patterns in pancreas of T2D patients. However, the underlying mechanisms remained largely unknown. We utilized human embryonic stem cells (hESC) as the in vitro model for studying the effects of hyperglycemia on DNA methylome and early pancreatic differentiation. Culture in hyperglycemic conditions disturbed the pancreatic lineage potential of hESC, leading to the downregulation of expression of pancreatic markers PDX1, NKX6−1 and NKX6−2 after in vitro differentiation. Genome-wide DNA methylome profiling revealed over 2000 differentially methylated CpG sites in hESC cultured in hyperglycemic condition when compared with those in control glucose condition. Gene ontology analysis also revealed that the hypermethylated genes were enriched in cell fate commitment. Among them, NKX6−2 was validated and its hypermethylation status was maintained upon differentiation into pancreatic progenitor cells. We also established mouse ESC lines at both physiological glucose level (PG-mESC) and conventional hyperglycemia glucose level (HG-mESC). Concordantly, DNA methylome analysis revealed the enrichment of hypermethylated genes related to cell differentiation in HG-mESC, including Nkx6−1. Our results suggested that hyperglycemia dysregulated the epigenome at early fetal development, possibly leading to impaired pancreatic development.

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Schmidtlein, Paula M., Clara Volz, Rüdiger Braun, Isabel Thürling, Olha Lapshyna, Ulrich F. Wellner, Björn Konukiewitz, Hendrik Lehnert, Jens-Uwe Marquardt, and Hendrik Ungefroren. "A Comparative Endocrine Trans-Differentiation Approach to Pancreatic Ductal Adenocarcinoma Cells with Different EMT Phenotypes Identifies Quasi-Mesenchymal Tumor Cells as Those with Highest Plasticity." Cancers 13, no. 18 (September 17, 2021): 4663. http://dx.doi.org/10.3390/cancers13184663.

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Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive and therapy-resistant cancer types which is largely due to tumor heterogeneity, cancer cell de-differentiation, and early metastatic spread. The major molecular subtypes of PDAC are designated classical/epithelial (E) and quasi-mesenchymal (QM) subtypes, with the latter having the worst prognosis. Epithelial–mesenchymal transition (EMT) and the reverse process, mesenchymal-epithelial transition (MET), are involved in regulating invasion/metastasis and stem cell generation in cancer cells but also early pancreatic endocrine differentiation or de-differentiation of adult pancreatic islet cells in vitro, suggesting that pancreatic ductal exocrine and endocrine cells share common EMT programs. Using a panel of PDAC-derived cell lines classified by epithelial/mesenchymal expression as either E or QM, we compared their trans-differentiation (TD) potential to endocrine progenitor or β cell-like cells since studies with human pancreatic cancer cells for possible future TD therapy in PDAC patients are not available so far. We observed that QM cell lines responded strongly to TD culture using as inducers 5′-aza-2′-deoxycytidine or growth factors/cytokines, while their E counterparts were refractory or showed only a weak response. Moreover, the gain of plasticity was associated with a decrease in proliferative and migratory activities and was directly related to epigenetic changes acquired during selection of a metastatic phenotype as revealed by TD experiments using the paired isogenic COLO 357-L3.6pl model. Our data indicate that a QM phenotype in PDAC coincides with increased plasticity and heightened trans-differentiation potential to activate a pancreatic β cell-specific transcriptional program. We strongly assume that this specific biological feature has potential to be exploited clinically in TD-based therapy to convert metastatic PDAC cells into less malignant or even benign cells.

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Attali, M., V. Stetsyuk, A. Basmaciogullari, V. Aiello, M. A. Zanta-Boussif, B. Duvillie, and R. Scharfmann. "Control of -Cell Differentiation by the Pancreatic Mesenchyme." Diabetes 56, no. 5 (February 23, 2007): 1248–58. http://dx.doi.org/10.2337/db06-1307.

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Murtaugh, L. C., B. Z. Stanger, K. M. Kwan, and D. A. Melton. "Notch signaling controls multiple steps of pancreatic differentiation." Proceedings of the National Academy of Sciences 100, no. 25 (December 1, 2003): 14920–25. http://dx.doi.org/10.1073/pnas.2436557100.

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Longnecker, Daniel S., James D. Jamieson, and Harold L. Asch. "Regulation of Growth and Differentiation in Pancreatic Cancer." Pancreas 4, no. 2 (April 1989): 256–75. http://dx.doi.org/10.1097/00006676-198904000-00016.

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Pour, Parviz M., Bruno M. Schmieda, Alexis B. Ulrich, Helmut Friess, Åke Andrén-Sandberg, and Markus W. Büchler. "Abnormal Differentiation of Islet Cells in Pancreatic Cancer." Pancreatology 1, no. 2 (January 2001): 110–16. http://dx.doi.org/10.1159/000055802.

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De La O, Jean–Paul, and L. Charles Murtaugh. "Notch Signaling: Where Pancreatic Cancer and Differentiation Meet?" Gastroenterology 136, no. 5 (May 2009): 1499–502. http://dx.doi.org/10.1053/j.gastro.2009.03.022.

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Sanchez, Didier, Cathy M. Mueller, and Michael E. Zenilman. "Pancreatic Regenerating Gene I and Acinar Cell Differentiation." Pancreas 38, no. 5 (July 2009): 572–77. http://dx.doi.org/10.1097/mpa.0b013e3181a1d9f9.

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Journal articles on the topic 'Pancreatic differentiation'

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