Madsen, O.D. and P. Serup. 2006. Towards cell <strong>the</strong>rapy for diabetes. Nat Biotechnol 24: 1481-3.Maehr, R., S. Chen, M. Snitow, T. Ludwig, L. Yagasaki, R. Goland, R.L. Leibel, and D.A. Melton.2009. Generation <strong>of</strong> pluripotent stem <strong>cells</strong> from patients with type 1 diabetes. Proc Natl AcadSci U S A 106: 15768-73.Mart<strong>in</strong>, G.R. 1981. Isolation <strong>of</strong> a pluripotent cell l<strong>in</strong>e from early <strong>mouse</strong> embryos cultured <strong>in</strong> mediumconditioned by teratocarc<strong>in</strong>oma stem <strong>cells</strong>. Proc Natl Acad Sci U S A 78: 7634-8.Mason, I. 2007. Initiation to end po<strong>in</strong>t: <strong>the</strong> multiple roles <strong>of</strong> fibroblast growth factors <strong>in</strong> neuraldevelopment. Nat Rev Neurosci 8: 583-96.McCall, M.D., C. Toso, E.E. Baetge, and A.M. Shapiro. 2010. Are stem <strong>cells</strong> a cure for diabetes? Cl<strong>in</strong>Sci (Lond) 118: 87-97.Meier, J.J., A. Bhushan, A.E. Butler, R.A. Rizza, and P.C. Butler. 2005. Susta<strong>in</strong>ed beta cell apoptosis <strong>in</strong>patients with long-stand<strong>in</strong>g type 1 diabetes: <strong>in</strong>direct evidence for islet regeneration?Diabetologia 48: 2221-8.Mfopou, J.K., B. Chen, I. Mateizel, K. Sermon, and L. Bouwens. 2010. Nogg<strong>in</strong>, ret<strong>in</strong>oids, and fibroblastgrowth factor regulate hepatic or pancreatic fate <strong>of</strong> human embryonic stem <strong>cells</strong>.Gastroenterology.Mfopou, J.K., V. De Groote, X. Xu, H. Heimberg, and L. Bouwens. 2007. Sonic hedgehog and o<strong>the</strong>rsoluble factors from differentiat<strong>in</strong>g embryoid bodies <strong>in</strong>hibit pancreas development. Stem Cells25: 1156-65.Micallef, S.J., M.E. Janes, K. Knezevic, R.P. Davis, A.G. Elefanty, and E.G. Stanley. 2005. Ret<strong>in</strong>oicacid <strong>in</strong>duces Pdx1-positive endoderm <strong>in</strong> differentiat<strong>in</strong>g <strong>mouse</strong> embryonic stem <strong>cells</strong>. Diabetes54: 301-5.Micallef, S.J., X. Li, M.E. Janes, S.A. Jackson, R.M. Su<strong>the</strong>rland, A.M. Lew, L.C. Harrison, A.G.Elefanty, and E.G. Stanley. 2007. Endocr<strong>in</strong>e <strong>cells</strong> develop with<strong>in</strong> pancreatic bud-like structuresderived from <strong>mouse</strong> <strong>ES</strong> <strong>cells</strong> differentiated <strong>in</strong> response to BMP4 and ret<strong>in</strong>oic acid. Stem CellRes 1: 25-36.M<strong>in</strong>, H., D.M. Danilenko, S.A. Scully, B. Bolon, B.D. R<strong>in</strong>g, J.E. Tarpley, M. DeRose, and W.S.Simonet. 1998. Fgf-10 is required for both limb and lung development and exhibits strik<strong>in</strong>gfunctional similarity to Drosophila branchless. Genes Dev 12: 3156-61.Mitsui, K., Y. Tokuzawa, H. Itoh, K. Segawa, M. Murakami, K. Takahashi, M. Maruyama, M. Maeda,and S. Yamanaka. 2003. The homeoprote<strong>in</strong> Nanog is required for ma<strong>in</strong>tenance <strong>of</strong> pluripotency<strong>in</strong> <strong>mouse</strong> epiblast and <strong>ES</strong> <strong>cells</strong>. Cell 113: 631-42.Mohammadi, M., S. Froum, J.M. Hamby, M.C. Schroeder, R.L. Panek, G.H. Lu, A.V. Eliseenkova, D.Green, J. Schless<strong>in</strong>ger, and S.R. Hubbard. 1998. Crystal structure <strong>of</strong> an angiogenesis <strong>in</strong>hibitorbound to <strong>the</strong> <strong>FGF</strong> receptor tyros<strong>in</strong>e k<strong>in</strong>ase doma<strong>in</strong>. Embo J 17: 5896-904.Mohammadi, M., G. McMahon, L. Sun, C. Tang, P. Hirth, B.K. Yeh, S.R. Hubbard, and J. Schless<strong>in</strong>ger.1997. Structures <strong>of</strong> <strong>the</strong> tyros<strong>in</strong>e k<strong>in</strong>ase doma<strong>in</strong> <strong>of</strong> fibroblast growth factor receptor <strong>in</strong> complexwith <strong>in</strong>hibitors. Science 276: 955-60.Morrisey, E.E., Z. Tang, K. Sigrist, M.M. Lu, F. Jiang, H.S. Ip, and M.S. Parmacek. 1998. GATA6regulates HNF4 and is required for <strong>differentiation</strong> <strong>of</strong> visceral endoderm <strong>in</strong> <strong>the</strong> <strong>mouse</strong> embryo.Genes Dev 12: 3579-90.Morrison, G.M., I. Oikonomopoulou, R.P. Migueles, S. Soneji, A. Livigni, T. Enver, and J.M.Brickman. 2008. Anterior def<strong>in</strong>itive endoderm from <strong>ES</strong>Cs reveals a role for <strong>FGF</strong> signal<strong>in</strong>g. CellStem Cell 3: 402-15.Moscatelli, D. 1987. High and low aff<strong>in</strong>ity b<strong>in</strong>d<strong>in</strong>g sites for basic fibroblast growth factor on cultured<strong>cells</strong>: absence <strong>of</strong> a role for low aff<strong>in</strong>ity b<strong>in</strong>d<strong>in</strong>g <strong>in</strong> <strong>the</strong> stimulation <strong>of</strong> plasm<strong>in</strong>ogen activatorproduction by bov<strong>in</strong>e capillary endo<strong>the</strong>lial <strong>cells</strong>. J Cell Physiol 131: 123-30.Mukhopadhyay, D., L. Tsiokas, and V.P. Sukhatme. 1998. High cell density <strong>in</strong>duces vascularendo<strong>the</strong>lial growth factor expression via prote<strong>in</strong> tyros<strong>in</strong>e phosphorylation. Gene Expr 7: 53-60.Ng, E.S., L. Azzola, K. Sourris, L. Robb, E.G. Stanley, and A.G. Elefanty. 2005. The primitive streakgene Mixl1 is required for efficient haematopoiesis and BMP4-<strong>in</strong>duced ventral mesodermpattern<strong>in</strong>g <strong>in</strong> differentiat<strong>in</strong>g <strong>ES</strong> <strong>cells</strong>. Development 132: 873-84.Nichols, J., J. Silva, M. Roode, and A. Smith. 2009. Suppression <strong>of</strong> Erk <strong>signall<strong>in</strong>g</strong> promotes ground statepluripotency <strong>in</strong> <strong>the</strong> <strong>mouse</strong> embryo. Development 136: 3215-22.Nichols, J. and A. Smith. 2009. Naive and primed pluripotent states. Cell Stem Cell 4: 487-92.Nichols, J., B. Zevnik, K. Anastassiadis, H. Niwa, D. Klewe-Nebenius, I. Chambers, H. Scholer, and A.Smith. 1998. Formation <strong>of</strong> pluripotent stem <strong>cells</strong> <strong>in</strong> <strong>the</strong> mammalian embryo depends on <strong>the</strong>POU transcription factor Oct4. Cell 95: 379-91.96
Nishikawa, S.I., S. Nishikawa, M. Hirashima, N. Matsuyoshi, and H. Kodama. 1998. Progressivel<strong>in</strong>eage analysis by cell sort<strong>in</strong>g and culture identifies FLK1+VE-cadher<strong>in</strong>+ <strong>cells</strong> at a diverg<strong>in</strong>gpo<strong>in</strong>t <strong>of</strong> endo<strong>the</strong>lial and hemopoietic l<strong>in</strong>eages. Development 125: 1747-57.Niswander, L. and G.R. Mart<strong>in</strong>. 1992. Fgf-4 expression dur<strong>in</strong>g gastrulation, myogenesis, limb and toothdevelopment <strong>in</strong> <strong>the</strong> <strong>mouse</strong>. Development 114: 755-68.Niwa, H. 2007. How is pluripotency determ<strong>in</strong>ed and ma<strong>in</strong>ta<strong>in</strong>ed? Development 134: 635-46.Niwa, H., T. Burdon, I. Chambers, and A. Smith. 1998. Self-renewal <strong>of</strong> pluripotent embryonic stem <strong>cells</strong>is mediated via activation <strong>of</strong> STAT3. Genes Dev 12: 2048-60.Ohtsuka, S. and S. Dalton. 2008. Molecular and biological properties <strong>of</strong> pluripotent embryonic stem<strong>cells</strong>. Gene Ther 15: 74-81.Ohuchi, H., Y. Hori, M. Yamasaki, H. Harada, K. Sek<strong>in</strong>e, S. Kato, and N. Itoh. 2000. <strong>FGF</strong>10 acts as amajor ligand for <strong>FGF</strong> receptor 2 IIIb <strong>in</strong> <strong>mouse</strong> multi-organ development. Biochem Biophys ResCommun 277: 643-9.Okada, Y., T. Shimazaki, G. Sobue, and H. Okano. 2004. Ret<strong>in</strong>oic-acid-concentration-dependentacquisition <strong>of</strong> neural cell identity dur<strong>in</strong>g <strong>in</strong> vitro <strong>differentiation</strong> <strong>of</strong> <strong>mouse</strong> embryonic stem <strong>cells</strong>.Dev Biol 275: 124-42.Okuno, M., K. M<strong>in</strong>ami, A. Okumachi, K. Miyawaki, N. Yokoi, S. Toyokuni, and S. Se<strong>in</strong>o. 2007.Generation <strong>of</strong> <strong>in</strong>sul<strong>in</strong>-secret<strong>in</strong>g <strong>cells</strong> from pancreatic ac<strong>in</strong>ar <strong>cells</strong> <strong>of</strong> animal models <strong>of</strong> type 1diabetes. Am J Physiol Endocr<strong>in</strong>ol Metab 292: E158-65.Omer, A., V. Duvivier-Kali, J. Fernandes, V. Tchipashvili, C.K. Colton, and G.C. Weir. 2005. Longtermnormoglycemia <strong>in</strong> rats receiv<strong>in</strong>g transplants with encapsulated islets. Transplantation 79:52-8.Ornitz, D.M. 2000. <strong>FGF</strong>s, heparan sulfate and <strong>FGF</strong>Rs: complex <strong>in</strong>teractions essential for development.Bioessays 22: 108-12.Ornitz, D.M. and N. Itoh. 2001. Fibroblast growth factors. Genome Biol 2: REVIEWS3005.Ornitz, D.M., J. Xu, J.S. Colv<strong>in</strong>, D.G. McEwen, C.A. MacArthur, F. Coulier, G. Gao, and M. Goldfarb.1996. Receptor specificity <strong>of</strong> <strong>the</strong> fibroblast growth factor family. J Biol Chem 271: 15292-7.Parameswaran, M. and P.P. Tam. 1995. Regionalisation <strong>of</strong> cell fate and morphogenetic movement <strong>of</strong> <strong>the</strong>mesoderm dur<strong>in</strong>g <strong>mouse</strong> gastrulation. Dev Genet 17: 16-28.Pawson, T. 1995. Prote<strong>in</strong>-tyros<strong>in</strong>e k<strong>in</strong>ases. Gett<strong>in</strong>g down to specifics. Nature 373: 477-8.Pease, S., P. Braghetta, D. Gear<strong>in</strong>g, D. Grail, and R.L. Williams. 1990. Isolation <strong>of</strong> embryonic stem (<strong>ES</strong>)<strong>cells</strong> <strong>in</strong> media supplemented with recomb<strong>in</strong>ant leukemia <strong>in</strong>hibitory factor (LIF). Dev Biol 141:344-52.Pellegr<strong>in</strong>i, G., P. Rama, F. Mavilio, and M. De Luca. 2009. Epi<strong>the</strong>lial stem <strong>cells</strong> <strong>in</strong> corneal regenerationand epidermal gene <strong>the</strong>rapy. J Pathol 217: 217-28.Plotnikov, A.N., J. Schless<strong>in</strong>ger, S.R. Hubbard, and M. Mohammadi. 1999. Structural basis for <strong>FGF</strong>receptor dimerization and activation. Cell 98: 641-50.Polk, D.B., G.W. McCollum, and G. Carpenter. 1995. Cell density-dependent regulation <strong>of</strong> PLC gamma1 tyros<strong>in</strong>e phosphorylation and catalytic activity <strong>in</strong> an <strong>in</strong>test<strong>in</strong>al cell l<strong>in</strong>e (IEC-6). J Cell Physiol162: 427-33.Posern, G., C.K. Weber, U.R. Rapp, and S.M. Feller. 1998. Activity <strong>of</strong> Rap1 is regulated by bombes<strong>in</strong>,cell adhesion, and cell density <strong>in</strong> NIH3T3 fibroblasts. J Biol Chem 273: 24297-300.Pye, D.A. and J.T. Gallagher. 1999. Monomer complexes <strong>of</strong> basic fibroblast growth factor and heparansulfate oligosaccharides are <strong>the</strong> m<strong>in</strong>imal functional unit for cell activation. J Biol Chem 274:13456-61.Qi, X., T.G. Li, J. Hao, J. Hu, J. Wang, H. Simmons, S. Miura, Y. Mish<strong>in</strong>a, and G.Q. Zhao. 2004. BMP4supports self-renewal <strong>of</strong> embryonic stem <strong>cells</strong> by <strong>in</strong>hibit<strong>in</strong>g mitogen-activated prote<strong>in</strong> k<strong>in</strong>asepathways. Proc Natl Acad Sci U S A 101: 6027-32.Ramiya, V.K., M. Maraist, K.E. Arfors, D.A. Schatz, A.B. Peck, and J.G. Cornelius. 2000. Reversal <strong>of</strong><strong>in</strong>sul<strong>in</strong>-dependent diabetes us<strong>in</strong>g islets generated <strong>in</strong> vitro from pancreatic stem <strong>cells</strong>. Nat Med 6:278-82.Rathjen, J., J.A. Lake, M.D. Bettess, J.M. Wash<strong>in</strong>gton, G. Chapman, and P.D. Rathjen. 1999. Formation<strong>of</strong> a primitive ectoderm like cell population, EPL <strong>cells</strong>, from <strong>ES</strong> <strong>cells</strong> <strong>in</strong> response to biologicallyderived factors. J Cell Sci 112 ( Pt 5): 601-12.Rhodes, C.J. 2005. Type 2 diabetes-a matter <strong>of</strong> beta-cell life and death? Science 307: 380-4.Ricordi, C. and H. Edlund. 2008. Toward a renewable source <strong>of</strong> pancreatic beta-<strong>cells</strong>. Nat Biotechnol 26:397-8.Robb, L. and P.P. Tam. 2004. Gastrula organiser and embryonic pattern<strong>in</strong>g <strong>in</strong> <strong>the</strong> <strong>mouse</strong>. Sem<strong>in</strong> CellDev Biol 15: 543-54.97
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PhD thesisCand.scient. Janny Marie
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ResuméSukkersyge er en sygdom der
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Table of contents1
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ICMinner cell massIdInhibitor of di
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cell mass regenerates probably thro
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Figure 1-1: Early embryo developmen
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Figure 1-3: Regional expression of
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The pluripotent stateThe pluripoten
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There are four membrane-bound FGFRs
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2. AimsThe aim of this study was to
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Figure S2Figure S2: A subpopulation
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- Page 96: AcknowledgementsThe work presented
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