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'Investigation of Factors That Prevent Endogenous Retinal Regeneration by Müller Stem Cells’

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'Investigation of factors that prevent endogenous retinal regeneration by Müller stem cells’ Karen Eastlake Thesis submitted to University College London for the degree of Doctor of Philosophy UCL Institute of Ophthalmology University College London February 2016 1 Acknowledgements This work would not have been possible without the support and encouragement of many people. I would like to thank Prof. Astrid Limb for her support and guidance over the past few years, and I am extremely grateful for her kind encouragement. I would also like to thank Prof. Peng Khaw for his support and guidance on the wider perspective of the research, and making me think outside of the little details. I would also like to thank Moorfields Trustees for their support which enabled me to perform this research. I would like to thank Kevin Mills and Wendy Heywood at the UCL Institute of Child health for the opportunity to work in their lab. Their help with all the proteomics methodologies and analysis has been invaluable. Thank you for making me so welcome. Special thanks to Emily Bliss from the same group whom helped me on numerous occasions. I would like to thank everyone, past and present, in the Müller group for their support, technical help and making work such a fun environment. Thank you Megan, Phillippa, Hari, Silke, Angshu, Erika, Na, Richard, Justin and Phey-Feng. It has been amazing working with you all. Lastly I would like to thank my family, whom have supported me no matter what, and giving me the encouragement to achieve anything, and a special thanks to Mat, for always being by my side. 2 Abstract In fish and amphibians, Müller glia are able to promote regeneration of the retina throughout adult life. Although these cells are present in the adult human retina, there is no evidence to suggest that regeneration in humans occurs following disease or injury. In Vitro, a population of human Müller glia has been described as possessing stem cell characteristics with the ability to proliferate and differentiate towards a neural phenotype. This may suggest that factors may be lost from the local retinal environment in the adult eye or that endogenous factors released during retinal disease may be inhibiting regeneration of the retina by this population of Müller glia. To investigate factors present during retinal pathologies and their involvement in endogenous regeneration, the proteomics profiles of human Müller glial stem cell (hMGSC) lines as well as normal cadaveric human retina and gliotic human retina, obtained from patients with proliferative vitreoretinopathy, were assessed by 2D difference gel electrophoresis (2D-DIGE) and Label Free Proteomics. In addition the protein profiles of zebrafish retina under normal, degenerated and regenerating conditions were assessed by the same methodology. Comparison of the protein profile in these tissues indicated a diverse reaction to injury, highlighting many differences and similarities between species. Some of these changes included proteins related to the extracellular matrix, cytoskeletal regulation, heat shock proteins and histones. The results demonstrated that there is complex protein regulation during gliosis, and some of the factors identified may constitute important targets for further investigations into the potential of Müller glia as a source of endogenous regeneration Cytokines and growth factors are known to play an important role in the progression of inflammation in retinal diseases. They are found in relatively low abundancy,and are small molecules that cannot be picked up by mass spectrometry techniques, therefore multiple cytokine immunoassays including dot-blot arrays as well as quantitative multiplex systems were used to analyse the levels of cytokines and growth factors in normal and gliotic human retina as well as hMGSC cultures. Analysis of the expression of inflammatory factors showed that in comparison with normal retina, gliotic retina exhibited greater than 2-fold increase in 24/102 factors examined by semi-quantitative arrays, and a significant increase in 19 out of 27 factors assessed by quantitative methods (p<0.05 to p<0.001). It was observed that 3 with the exception of some chemotactic factors, the majority of cytokines and inflammatory factors were produced by hMGSCs in vitro and included G-CSF, MCP- 1, PDGF-bb, RANTES, VEGF and TGFβ2. Heat shock proteins (HSPs) were identified to be highly altered in the gliotic human retina. Changes in the levels of various HSPs were also observed in the zebrafish retina. As HSPs play important roles in protein folding, the stress response, apoptosis and indirectly in many intracellular signalling pathways, they may be important with regard to Müller glia differentiation. The hMGSC line MIO-M1 was assessed for its ability to differentiate in the presence of a heat shock protein 70 inhibitor or heat shock protein 90 inhibitor. In addition, levels of the expression of HSP90 and HSp70 by MIO-M1 were examined following culture of these cells with pro-inflammatory cytokines. The Results showed that MIO-M1 culture with the pro- inflammatory factors IL-6, TGF and TNFα did not alter levels of HSP70 or HSP90 in these cells. Inhibition of HSP90 or HSP70 did not appear to modify differentiation of MIO-M1 towards photoreceptors. These observations suggest that high expression of HSPs in these cells may be linked to their stem cell like phenotype, and may indicate a resistance to stress which is observed in many other stem cell populations. Further investigation on the roles of heat shock proteins in these cells is required, in order to understand their roles in differentiation and regeneration of the human retina. In conclusion, the present study has identified key areas of interest and highlighted many targets that could be involved in endogenous regeneration of the adult human retina by Müller glia. It is hoped that future investigations will explore the involvement of such factors with regards to endogenous retinal repair mechanisms by Müller glia and drive the development of regenerative therapies to treat retinal diseases. 4 Chapter 1. General Introduction ......................................................................... 22 1.1 Anatomy of the eye .................................................................................. 23 1.2 Retinal Development and Histogenesis in the vertebrate retina ............... 28 1.3 Müller Glia ............................................................................................... 31 1.3.1 Location and Structure ...................................................................... 31 1.3.2 Müller glia development .................................................................... 31 1.3.3 Function ........................................................................................... 32 1.4 Retinal injury and regeneration ................................................................ 33 1.4.1 Endogenous regeneration of the Zebrafish retina ............................. 33 1.4.2 Retinal regeneration of the Chick retina ............................................ 36 1.4.3 Retinal regeneration in Mammals ..................................................... 37 1.4.4 Retinal Gliosis .................................................................................. 42 1.4.5 PVR .................................................................................................. 43 1.4.6 Summary and purpose of thesis ....................................................... 46 1.5 Objectives of this thesis ........................................................................... 48 Chapter 2. Proteomic profiling comparison between normal and gliotic human retina, and contribution of Müller stem cells, to these profiles. ............................... 49 2.1 Introduction .............................................................................................. 49 2.1.1 Retinal Gliosis and Müller glia ........................................................... 49 2.1.2 Müller glia as stem cells in the mammalian retina ............................. 51 2.1.3 Proliferative vitreoretinopathy (PVR) as a model of retinal gliosis ..... 53 2.1.4 Proteomic studies in PVR ................................................................. 54 2.2 Objectives and experimental Design ........................................................ 56 2.3 Results .................................................................................................... 59 2.3.1 Human tissue and degree of PVR .................................................... 59 2.3.2 Protein abundancies determined by Mass spectrometry analysis of normal and gliotic human retina and Müller glial cell lines. .............................. 59 2.3.3 Comparison of protein expression between normal human cadaveric retina and gliotic retina derived from PVR patients. ......................................... 62 2.3.4 Pathway analysis of differentially expressed proteins between the normal and gliotic human retina. ..................................................................... 73 2.3.5 Comparative analysis of protein expression between normal and gliotic retina and Müller glia as examined by 2D-DIGE. .................................. 77 2.3.6 Protein profile of Müller glia as identified by gene ontology classification and enrichment. ......................................................................... 80 2.3.7 MIO-M1 profile and patterns of protein expression during retinal ganglion cell differentiation. ...........................................................................
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