TRANSPLANTATION AND IMPROVEMENT OF MOUSE EMBRYO PROGENITOR-DERIVED INSULIN-PRODUCING CELLS FOR TYPE DIABETES THERAPY SHAO SHIYING NATIONAL UNIVERSITY OF SINGAPORE 2010 TRANSPLANTATION AND IMPROVEMENT OF MOUSE EMBRYO PROGENITOR-DERIVED INSULIN-PRODUCING CELLS FOR TYPE DIABETES THERAPY SHAO SHIYING (M.Sc., TONGJI University) A THESIS SUBMITTED FOR THE DEGREE OF PHILOSOPHY OF DOCTORATE NATIONAL UNIVERISTY OF MEDICAL INSTITUTES DEPARTMENT OF BIOCHEMISTRY NATIONAL UNIVERSITY OF SINGAPORE 2010 ACKNOWLEDGEMENTS First of all, I would like to express my sincere appreciation and thanks to my supervisor A/P Li Guodong for his invaluable guidance, support and encouragement during the course of this research This research would not have been possible without his insightful ideas Many thanks to all my fellow lab-mates, Ruihua, Jiping, Xiefei, Heqing, Michelle, Gao Yun and Xie Bing in NUMI for the useful discussion sessions that helped me throughout the research My appreciation also goes out to my friends, Bai Jie, Zhu Yi, Hanfeng, Tiannan, Shugui, Niandan, Tangmei and Li Xi who helped me tremendously all along and provided me with many useful inspirations Special thanks to my devoted parents and sister Qin, who offered me with never ending supports, encouragements and the very academic foundations that make everything possible Finally, I would like to thank the National University of Singapore for facilities and generous financial support that makes this research project a success i PUBLICATION LIST Full papers: Shiying Shao, Yun Gao, Bing Xie, Fei Xie, Sai Kiang Lim, GuoDong Li (2011) Correction of hyperglycemia in type diabetic models by transplantation of encapsulated insulin-producing cells derived from mouse embryo progenitor J Endocrinol 208:245-255, e-pub http://dx.doi.org/10.1530/JOE-10-0378 Shiying Shao, Yun Gao, Ruihua Luo, Wataru Nishimura, Arun Sharma, GuoDong Li Improvement of insulin-producing cells derived from mouse embryo progenitor by enhancement of MafA expression Manuscript to be submitted Conference papers: Shao S, Gao Y, Xie B, Lim SK, Li GD (2010) Optimization of mouse embryo progenitor-derived insulin-producing cells for diabetes treatment Poster presentation at the 8th ISSCR Annual Meeting, 16-19 June, 2010, San Francisco, USA Shao S, Li GD (2009) Improvement of mouse embryo progenitor-derived insulin-producing cells for type diabetes therapy Poster presentation at 49th Annual Meeting of American Society for Cell Biology, 5-9 December 2009, San Diego, USA Mol Biol Cell 20(suppl.):#116/B63 (online) Shao S, Wu H, Lim SK, Li GD (2009) Fate of encapsulated insulin-producing cells derived from mouse embryonic progenitor cells following transplantation in immune competent diabetic mice In: Friday Poster Session Abstracts Book, p.21 Presented at the 7th ISSCR Annual Meeting, 8-11 July, 2009, Barcelona, Spain Shao S, Xie F, Li GD (2008) Functional characterization in vivo and in vitro of encapsulated insulin-producing cells derived from mouse embryo progenitor Diabetologia 51 (suppl 1):S182 Poster at 44th Annual Meeting of the European Association for the Study of Diabetes (EASD), 7-11 Sep 2008, Rome, Italy Li GD, Shao S, Xie F, Luo R, Wu H (2008) Functional assessment of mouse ESCand progenitor-derived insulin-producing cells following encapsulation and transplantation in type diabetic animals In: Poster Session Abstracts book, p.151 Presented at the 6th ISSCR Annual Meeting, 11-14 June, 2008, Philadelphia, PA, USA Shao S, Xie F, Luo R, Salto-Tellez M, Lim SK, Li GD (2007) Transplantation of encapsulated embryonic progenitor-derived insulin-producing cells reverses hyperglycemia in immune-competent diabetic animals Presented at 67th ADA Annual Scientific Sessions, 21-26 June, 2007, Chicago, IL, USA Diabetes 56(suppl 1): A520 ii TABLE OF CONTENTS ACKNOWLEDGEMENTS i PUBLICATIONS ii TABLE OF CONTENTS iii SUMMARY .vii TABLES AND FIGURES viii ABBREVIATIONS x CHAPTER INTRODUCTION 1.1 General background .2 1.1.1 Diabetes mellitus and traditional therapy…………………………… …2 1.1.2 Islets of Langerhans and -cell function………… …………………….3 1.1.3 Glucose-stimulated insulin secretion ……………………………….… 1.1.4 Insulin secretion regulation…………………………….……………… 1.2 Transplantation therapy for type diabetes…………………….……………9 1.2.1 Human islet transplantation for type diabetes mellitus…………… …9 1.2.2 Substitute -cell therapy for type diabetes mellitus………………….11 1.2.3 Characteristics of mouse embryo progenitor derived insulin-producing cells………………………………………………………… ………………13 1.2.4 Transplantation of MPEI-1 cells in immune-deficient mice………… 14 1.2.5 Microencapsulation techniques……………………………………… 15 1.2.5.1 Ratinale of encapsulation of cells……………………………… 15 1.2.5.2 Principle and application of encapsulation……………………… 16 1.3 Roles of Maf A in -cell development and function.…………………… 19 1.3.1 GSIS-related genes in -cells………………………………………… 19 1.3.2 Transcription factors regulating GSIS-related genes ……… 20 1.3.3 Subtypes of Maf family………………………… ……………………21 1.3.4 Regulatory elements controlling insulin gene transcription …………22 1.3.5 Characters and role of MafA…………………………… ………… 23 1.3.6 Regulation of MafA…………………… …………………………… 25 1.4 Aim and significance of the study……… ……………………………… 25 CHAPTER MATERIALS AND METHODS 2.1 Materials……………………………………………… ………………….30 2.2 Methods for microencapsulation and transplantation…………… …… 33 2.2.1 MEPI-1cell culture and storage……………………………… ………33 2.2.2 Microencapsulation………………………………… ……………… 34 2.2.3 Transplantation and washing-out of capsules………………… …… 35 2.2.4 Measurement of insulin secretion of microcapsules ………… …… 36 2.2.5 Measurement of cell number in microcapsule………………… …… 37 2.2.5.1 DNA content detection 37 iii 2.2.5.2 Insulin content determination 37 2.2.6 Immunohistochemistry……………………… ……………………….37 2.2.6.1 Brdu staining……………………… …………………………… 37 2.2.6.2 Insulin staining……………………………………… ……………38 2.2.6.3 H&E staining……………………………………… …………… 38 2.2.7 Permeability detection of microcapsules………………………… … 39 2.2.8 Determination of plasma insulin……………….………………… ….39 2.2.9 Oral glucose tolerance Test (OGTT)…………………….………… …39 2.2.10 Cytokine measurement…………………………………………… …39 2.3 Methods for experiments on MafA ……………………… …………… 40 2.3.1 Molecular biology……………………… …………………………….40 2.3.1.1 E.Coli transformaotion………………………………… …………40 2.3.1.2 Plasmid DNA preparation……………………………… ……… 40 2.3.1.3 Construction of recombinant lentiviral vectors containing mouse MafA cDNA……………………………………………………… 41 2.3.1.3.1 Hotstar hifidelity PCR…………………………………….……41 2.3.1.3.2 Restriction enzyme digestion…………………………… ……42 2.3.1.3.3 Construction of entry clone PENTR3C-MafA…………………42 2.3.1.3.4 LR recombination………………………………………………43 2.3.1.3.5 pLenti-MafA virus collection and storage……………… ……43 2.3.1.4 Up-regulation of MafA in MEPI-1 cells……… …………… … 44 2.3.1.4.1 Transient up-regulation of MafA in MEPI-1 cells… …… ….44 2.3.1.4.2 Stable up-regulation of MafA in MEPI-1 cells……… ……….44 2.3.2 mRNA assay………………………………………………… ……….45 2.3.2.1 RNA purification……………………………………… …………45 2.3.2.2 Reverse transcription……………………………………… …… 45 2.3.2.3 Polymerase chains reaction…………………………………… ….46 2.3.2.4 Real-time RT-PCR………………………… ………………….…47 2.3.3 Protein assay………………………………… ……………………….47 2.3.3.1 Protein extraction…………………………………… ……………47 2.3.3.2 Measurement of protein concentrations…………………… …… 48 2.3.3.3 Western blotting………………………………………… ……… 48 2.3.4 Measurement of insulin secretion and content in cell monolayer.…… 50 2.3.5 Measurement of membrane potential………………… ………………51 2.3.6 Measurement of intracellular Ca2+ concentration……………… …….52 2.3.7 Glucose metabolism…………………………………………… …… 52 2.3.7.1 Assessment of glucose metabolism by MTS assay…………… ….52 2.3.7.2 Assessment of glucose metabolism by ATP detection……… … 53 2.3.8 Examination of cell growth and death…………………………… … 53 2.3.9 RT2 profiler PCR array…………………………………… ………….55 2.4 Statistical analysis…………………………………… ………………… 56 CHAPTER RESULTS 3.1 Transplantation of microencapsulated MEPI-1 cells in diabetic mice…… 58 3.1.1 Morphology of microcapsules in vitro and in vivo…………………….58 3.1.2 Glucose-stimulated insulin secretion in encapsulated cells.… ………59 3.1.3 Reversing hyperglycemia in diabetic mice by transplantation of encapsulated MEPI-1 cells…………… ………………………… …….… 61 3.1.3.1 Glucose levels after transplantation of MEPI-1 cells without encapsulation………… …………………………………….…………….61 iv 3.1.3.2 Glycemic changes after transplantation of encapsulated MEPI-1 cells……………………………………………………………………… 62 3.1.3.3 Effects of repeated transplantation of encapsulated MEPI-1 cells 65 3.1.3.4 Glycemic changes after washing out of transplanted microcapsules …………………………………………………………… 66 3.1.4 Properties of MEPI-1 cells in microcapsules…………………….…….67 3.1.4.1 Cell growth rate in vivo…………………………… … ……… 67 3.1.4.2 Cell growth rate in vitro……………… ……………… …………68 3.1.4.3 Correlation of cell growth and glycemic level… ……… …….…69 3.1.4.4 Cell population doubling time…………………… ………………72 3.1.5 Plasma insulin level in capsule-transplanted diabetic mice……… ….74 3.1.6 Oral glucose tolerance test in capsule-transplanted diabetic mice… …75 3.1.7 Histology of microcapsules in vivo and in vitro……………… …… 77 3.1.8 Permeability of microcapsules after transplantation in mice………… 79 3.1.9 Cytokine production in mice implanted with encapsulated MEPI-1 cells………………………………………………………………………… 80 3.2 The roles of MafA in MEPI-1 cells………………… …………………….82 3.2.1 Lower expression level of MafA in MEPI-1 cells………………… …82 3.2.1.1 MafA expression in MEPI-1 cells at mRNA and protein level……82 3.2.1.2 MafA expression in MEPI-1 cells by immunofluorescence staining………………………………………………………………… 85 3.2.2 MafA restoration improves MEPI-1 cell functions……………… … 86 3.2.2.1 MafA restoration increases glucose metabolism……………… ….86 3.2.2.2 MafA restoration enhances the depolarization of membrane potential upon glucose stimulation…… ………………………………………… 87 3.2.2.3 MafA restoration augments [Ca2+]i response…… … 89 3.2.2.4 MafA restoration increases insulin content …90 3.2.2.5 MafA restoration improves glucose-stimulated insulin secretion ….91 3.2.2.6 Effects of MafA restoration on ion fluxes and insulin secretion stimulated by non-nutrient secretagogues……………………….…….……92 3.2.4 MafA restoration enhances the expression profile of -cell specific genes…………………………………………………………………….… 95 3.2.5 MafA restoration reduces cell growth rate…………………………… 98 CHAPTER DISCUSSION 4.1 Transplantation of microencapsulated MEPI-1 cells corrects hyperglycemia in diabetic mice……………………………………………………………….101 4.1.1 Characteristics of alginate microcapsules……….……………….….103 4.1.2 Correction of hyperglycemia by repeated the transplantations for months…………… ……….………………….…………………… 105 4.1.3 Scenarios for hyperglycemia relapse after transplantation……………108 4.1.3.1 The optimal site for transplantation……… ……………… ……109 4.1.3.2 The permeability of transplanted microcapsule……………… 110 4.1.3.3 The immune reaction after microcapsule transplantation ………111 4.1.3.4 Behaviors of microencapsulated MEPI-1 cells.…………….……112 4.1.4 Immaturity of encapsulated MEPI-1 cells…….……………………113 4.1.5 Summary of transplantation of microencapsulated MEPI-1 cells…….116 4.2 Restoration of MafA in MEPI-1 cells………………….……….……… 116 4.2.1 Less-physical characteristics of MEPI-1 cells…………….…………117 4.2.2 MafA up-regulation improves GSIS and related signaling events in v MEPI-1 cells…………………………………….…………………….….…118 4.2.3 The role of MafA in cAMP-involved pathway in MEPI-1 cells…… 123 4.2.4 MafA restoration reduces proliferation of MEPI-1cells………… … 123 4.2.5 MafA up-regulation promotes gene expression profile in MEPI-1 cells…………………………………………………………………….……124 4.2.6 Summary of studies of MafA in MEPI-1 cells…….……………….…128 4.3 Conclusions……………………………………………………………….129 4.4 Future work…………………………………………………… …… …130 REFERENCE LIST……………………………… …………… …… …132 vi SUMMARY The application of islet transplantation to cure type diabetics is impeded by shortage of cadaveric pancreata and requirement of life-long immunosuppression In this thesis study, expandable insulin-producing MEPI-1 cells derived from mouse embryonic progenitor were immuno-isolated by microencapsulation After peritoneal transplantation of encapsulated MEPI-1 cells in streptozotocin-induced diabetic mice, normoglycemia or moderate hypoglycemia was achieved for 2.5 months before a relapse of hyperglycemia Importantly, a second transplantation in relapsed mice was as effective in correcting hyperglycemia as in the first one The relapse could be due to necrosis resulting from a slow increase of cell mass by proliferation To improve MEPI-1 cell maturation toward mature primary -cells, the level of MafA, a key transcription factor for promoting -cell maturation but expressed low in MEPI-1 cells, was restored by infection of lentivirus expressing MafA MafA-restored MEPI-1 cells up-regulated expression of genes for many molecules important for -cell function, slowed cell proliferation, enhanced insulin content, lowered basal insulin release but markedly improved glucose-induced insulin secretion These data demonstrated a promising way for the treatment of type diabetics using embryonic stem cells as the -cell source while preventing immunosuppression via immune-isolation of cells vii TABLES AND FIGURES Fig I Schematic diagram of insulin synthesis and release in -cells………… …5 Fig II Scheme of glucose-stimulated insulin release from -cells……………….…7 Fig III Key transcription factors involved in insulin gene transcription………… 24 Fig IV Genes regulated by MafA…………………………………………………24 Fig V Procedure and setup for microencapsulation of cells……………………….35 Fig VI The main implantation sites employed in cell encapsulation technology.110 Table Materials and sources 30 Table Program of Hotstar Hifidelity PCR………………………………………42 Table Programs of RT-PCR and real-time PCR…………………………………46 Table Primers used for SYBR Green based real-time PCR…………………… 46 Table Gel compositions for SDS-PAGE……………………………… ……….50 Table Conditions of critical factors in Western blotting …………………………50 Table Program of RT2 reaction………………………………………………….56 Table Cytokines in peritoneal fluid after transplantation of encapsulated MEPI-1 cells…………………………………………………………………………………81 Fig Barium alginate-made capsules both in vitro and in vivo.…………… .59 Fig Insulin secretion from encapsulated MEPI-1 cells………………………….60 Fig Reversing hyperglycemia in STZ-induced immune-competent diabetic mice by transplantation (Tx) of MEPI-1 cells without encapsulation………………… 62 Fig Reversing hyperglycemia in STZ-induced immune-competent diabetic mice by transplantation (Tx) of encapsulated MEPI-1 cells…………………………… 64 Fig Reversing hyperglycemia in STZ-induced immune-competent diabetic mice by repeated transplantations of encapsulated MEPI-1 cells……………………… 65 Fig Transplantation and wash-out of encapsulated MEPI-1 cells in STZ-induced immune-competent diabetic mice… ………………………………66 Fig Growth of encapsulated MEPI-1 cells after transplantation in STZ-treated diabetic mice……………………………………… ………………………………68 Fig Growth of encapsulated MEPI-1 cells after culture in vitro …………… 69 Fig The relationship of growth of encapsulated MEPI-1 cells and glycemic levels after transplantation in STZ-treated mice…… ……………………………71 Fig 10 Cell population doubling time in capsules………………… ……………73 Fig 11 Plasma insulin in mice at different intervals after transplantation of encapsulated MEPI-1 cells…………………………………………………………74 Fig 12 OGTT in mice at different intervals after transplantation of encapsulated MEPI-1 cells……………………………………………………………………… 76 Fig 13 Histology of encapsulated MEPI-1 cells in vivo and in vitro… …………78 Fig 14 DAPI staining and permeability of washed-out capsules…………………79 Fig 15 MafA expression in MEPI-1 cells at mRNA and protein levels……… 84 Fig 16 Assessment of MafA expression level by immunofluorescence staining 85 Fig 17 Glucose metabolism in MafA-upregulated MEPI-1 cells…………………87 Fig 18 Membrane potential in pLenti-DEST and pLenti-MafA MEPI-1 cells… 88 Fig 19 Responses of [Ca2+]i in pLenti-DEST and pLenti-MafA MEPI-1 cells… 89 Fig 20 Insulin content in pLenti-MafA and pLenti-MafA-m1 MEPI-1 cells…… 90 Fig 21 Glucose-stimulated insulin secretion in MafA-upregulated MEPI-1 cells.92 Fig 22 Membrane potential, [Ca2+]i and insulin secretion in MafA-restored MEPI-1 cells……………………………………………………………………… 94 viii Chapter Discussion 4.4 Future work To date, the reported substitute insulin-producing cells from stem cells failed to fulfil the criteria for replacement therapy of type diabetes In our lab, a dozen of new surrogate -cell lines have been generated One part of my work has been focusing on the assessment of the in vivo function of one such insulin-producing cell line, MEPI-1, in immune competent diabetic mice Another part of my work aimed to improve these cells by up-regulation of a key transcription factor important for -cell maturation and function The issues remained to be further investigated are listed below: Microcapsule is a useful tool which could prevent host immune rejection; nevertheless, the non-biocompatibility of the materials could still stimulate fibrotic growth More biocompatible materials are necessary to be tested or developed to decrease the non-specific inflammation and facilitate the supply of nutrients and oxygen to the cells in capsules Because of immaturity, encapsulated MEPI-1 cells caused hypoglycaemia after transplantation and the relapse of hyperglycemia could not be circumvented MafA up-regulation of MEPI-1 cells could decrease proliferation and improve GSIS in the in vitro studies It would be interesting to transplant MafA-restored MEPI-1 cells in diabetic animals to see if these more mature cells would also exhibit improved function in vivo, i.e less hypoglycemia and longer correction of hyperglycemia MafA-upregulated MEPI-1 cells displayed reduced proliferation rate but the underlying mechanism is unclear Thus the possible effects on the regulators involved in 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2.3 Characteristics of mouse embryo progenitor derived. . .TRANSPLANTATION AND IMPROVEMENT OF MOUSE EMBRYO PROGENITOR- DERIVED INSULIN- PRODUCING CELLS FOR TYPE DIABETES THERAPY SHAO SHIYING (M.Sc., TONGJI University) A THESIS SUBMITTED FOR THE