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Stem Cells from Patients with Congenital Hyperinsulinism

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Stem Cells from Patients with Congenital Hyperinsulinism Stem cells from patients with Congenital Hyperinsulinism A thesis submitted to the University of Manchester for the degree of doctor of philosophy in the Faculty of Biology, Medicine and Health School of Medical Sciences Sophie Grace Kellaway 2016 Contents 0.1 Abbreviations . 9 0.2 Abstract . 11 0.3 Declaration . 12 0.4 Copyright statement . 12 0.5 Acknowledgements . 13 0.6 Thesis organisation . 14 0.7 Author note . 15 1 Literature Review 16 1.1 Introduction . 16 1.2 The Pancreas . 17 1.2.1 Anatomy . 17 1.2.2 Development . 20 1.2.3 Post developmental endocrine proliferation . 23 1.2.4 Cell cycle in the pancreas . 23 1.2.5 Signalling and markers . 25 1.3 Congenital hyperinsulinism (CHI) . 27 1.3.1 Symptoms and causes . 27 1.3.2 Hyperproliferation . 30 1.3.3 Treatment . 30 1.3.4 Experimental models . 30 1.4 Diabetes . 31 1.4.1 Epidemiology . 31 1.4.2 Pathogenesis . 32 1.4.3 Treatment . 33 1.5 Stem Cells . 34 1.5.1 Pancreatic stem cells . 34 1.5.2 Mesenchymal stem cells . 35 2 1.5.3 Pluripotent stem cells . 38 1.5.4 Generation of iPSCs . 41 1.6 Aims . 43 1.7 References . 43 2 A Novel Source of Mesenchymal Stem Cells derived from the Pancreas of Patients with Congenital Hyperinsulinism. 64 2.1 Abstract . 65 2.2 Introduction . 66 2.3 Methods . 68 2.3.1 Derivation of CHI pancreatic mesenchymal stem cell (CHI pMSC) lines . 68 2.3.2 Cell culture . 68 2.3.3 Karyotyping . 69 2.3.4 Short tandem repeat (STR) profiling . 69 2.3.5 RT-PCR and qRT-PCR . 69 2.3.6 Genotyping . 70 2.3.7 Adipogenesis, osteogenesis and chondrogenesis . 72 2.3.8 Flow Cytometry . 73 2.3.9 Immunocytochemistry (ICC) . 73 2.3.10 Bisulfite sequencing . 75 2.4 Results . 76 2.4.1 MSCs were derived from three CHI patients . 76 2.4.2 Derived cells were karyotypically stable, unique and contained the CHI causing mutations . 83 2.4.3 CHI derived MSCs express pancreatic markers . 84 2.4.4 CHI pMSCs have altered gene expression and methylation patterns compared to bmMSCs . 88 2.5 Discussion . 94 2.6 References . 97 3 Increased Proliferation and Altered Cell Cycle Regulation in Pancreatic Stem Cells derived from Patients with Congenital Hyperinsulinism 104 3.1 Abstract . 105 3.2 Introduction . 106 3.3 Methods . 110 3.3.1 Cell culture . 110 3 3.3.2 Derivation of adult pancreatic mesenchymal stem cell (A pMSC) lines . 111 3.3.3 Flow Cytometry (propidium iodide) . 111 3.3.4 Immunocytochemistry (ICC) . 111 3.3.5 Western Blotting . 112 3.3.6 Ki67 stain and count . 112 3.4 Results . 114 3.4.1 Increased proliferation in CHI tissue and CHI-derived pMSCs . 114 3.4.2 Cell cycle regulation in CHI MSCs . 116 Kip1 3.4.3 Distribution of G1/S molecules - decreased nuclear p27 in CHI-derived pMSCs . 118 3.4.4 Distribution of G2/M molecules - possible increase of CDK1 in CHI-derived pMSCs . 120 3.4.5 Glucose and insulin affect p27Kip1 protein levels and localisation . 122 3.5 Discussion . 125 3.6 References . 128 4 Stem Cell Derived β-cells: a new resource for Congenital Hyperinsulinism? 134 4.1 Abstract . 135 4.2 Introduction . 136 4.3 Methods . 140 4.3.1 MSC culture . 140 4.3.2 Feeder dependent iPSC culture . 140 4.3.3 Feeder free iPSC culture . 141 4.3.4 Derivation of iPSCs . 141 4.3.5 Three germ layer iPSC differentiation . 141 4.3.6 MSC differentiation . 142 4.3.7 Differentiation: Melton/Kieffer . 142 4.3.8 RT-PCR and qRT-PCR . 144 4.3.9 Bisulfite sequencing . 146 4.3.10 Immunocytochemistry (ICC) . 147 4.3.11 Western blot . 148 4.3.12 Glucose-stimulated insulin secretion (GSIS) assay . 148 4.4 Results . 151 4.4.1 Serum withdrawal was insufficient to induce differentiation of CHI MSCs . 151 4.4.2 A step-wise differentiation protocol shows stage specific gene induction, en- hanced by the addition of DKK1 . 152 4 4.4.3 Phenotypic analysis of differentiated CHI pMSCs . 156 4.4.4 Spheroid formation was essential for differentiation . 160 4.4.5 Derivation of iPSCs . 161 4.4.6 Differentiation of CHI-iPSCs to definitive endoderm . 167 4.4.7 Differentiation of CHI-iPSCs to pancreatic endoderm . 168 4.4.8 Differentiation of CHI-iPSCs to hormone positive islet cells . 169 4.5 Discussion . ..
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