Investigation of factors that prevent endogenous regeneration of the retina by Müller stem cells

Lead Research Organisation: University College London
Department Name: Institute of Ophthalmology

Abstract

Adult human retina harbours a population of Müller cells with stem cell characteristics. Although these cells have the ability to grow and neurally differentiate in vitro, there is no evidence that they regenerate retina in vivo. It has been thought that factors released during reactive gliosis, a glial proliferation observed in all retinal degenerative conditions, are responsible for the inhibition of retinal regeneration by endogenous stem cells. The proposed research aims to identifiy factors that may promote neural regeneration of diseased retina by stimulating the endogenous proliferation and neural differentiation of Müller stem cells. Using proteomic approaches, we will investigate the total protein and cytokine expression profile of fragments of human gliotic retina, surgically removed as part of the treatment for complicated retinal detachment, and will compare this profile with that of normal cadaveric donor retina. Factors found to be selectively increased or decreased in degenerated retina will then be examined for their ability to inhibit or promote Müller stem cell growth and differentiation in vitro. Once candidate factors have been found to be active on the inhibition or promotion of these cell functions, we will confirm their roles by blocking or promoting their activities using agonist or antagonist molecules for these factors. The work will be undertaken in collaboration with Prof. Sun Xinghai and Dr Lei Yuan from the Eye Hospital at Fudan University, Shanghai. The proteomic analysis will be performed at the UCL Institute of Ophthalmology and is expected to identify candidate factors which can be examined by both the UK and the Fudan group on Müller stem cell growth and differentiation. The project will form part of a PhD training program for a Chinese student who will visit the UCL Institute of Ophthalmology for a year. Funding for her visit and that of Prof Sun and Dr Lei, her PhD supervisors, is being sought by the Fudan University group fthe Natural Science Foundation of China.

Technical Summary

Degeneration of retinal neurons is the ultimate cause of blindness resulting from prevalent conditions, such as age related macular degeneration (AMD), diabetic retinopathy (DR), end stage glaucoma, retinal detachment and retinitis pigmentosa. Although extensive research is being undertaken to replace damaged retinal neurons by neural stem cell transplantation, stimulation of endogenous proliferation and neural differentiation of retinal stem cells would be a preferred alternative to the transplantation approaches currently being investigated.
The research therefore aims to identify factors that may inhibit regeneration of diseased retina, and whose expression may be potentially altered to promote the endogenous proliferation and neural differentiation of Müller stem cells in situ. Using proteomic approaches, we will investigate the total protein and cytokine expression profile of fragments of human gliotic retina, surgically removed as part of the treatment for complicated retinal detachment, and will compare this profile with that of normal cadaveric retina. Factors selectively upregulated or downregulated in gliotic retina will be examined for their ability to inhibit or promote Müller stem cell growth and differentiation in vitro.
Candidate factors found to be active on the inhibition or promotion of these cell functions, will be further examined for their ability to block or promote stem cell activities using agonist or antagonist molecules for these factors. The work will be undertaken in collaboration with Prof. Sun Xinghai and Dr Lei Yuan from the Eye Hospital at Fudan University, Shanghai. The proteomic analysis will be performed at the UCL Institute of Ophthalmology and is expected to identify candidate factors which can be examined by both the UK and the Fudan group on Müller stem cell growth and differentiation. The project will form part of a PhD training program for a Chinese student who will visit the UCL Institute of Ophthalmology for a year.

Planned Impact

The proposal has direct relevance to the exploration of stem cell based therapies for human application. The research aims to develop treatments for ocular conditions affecting a very large number of individuals worldwide. Degeneration of retinal neurons is the ultimate cause of blindness resulting from prevalent ocular diseases, such as age related macular degeneration (AMD), diabetic retinopathy (DR), end stage glaucoma, retinal detachment and retinitis pigmentosa, amongst others. According to Vision 2020 (www.vision2020.org), a global initiative for the prevention of blindness, AMD affects approximately 25 to 30 million people over the age of 55 worldwide, whilst glaucoma affects 60 million individuals worldwide. With recent advances in laser and surgical treatments, it is possible to prevent substantial visual loss in many patients, but in a long term, it is impossible to prevent blindness finally occurring in many individuals. The proposed research will be focused on the identification of factors that may inhibit neural regeneration of diseased retina, whose expression may be potentially altered to promote the endogenous proliferation and neural differentiation of Müller stem cells within the retina. Stimulation of endogenous proliferation and neural differentiation to replace damaged neurons would be a preferred alternative to the transplantation procedures currently being investigated. If this approach could be implemented -an injection of a given factor will be preferred to retinal transplantation surgery- it will avoid the trauma of surgical procedures and could potentially be performed with minimal resources.

Publications

10 25 50

publication icon
Chandra A (2013) Gene expression and protein distribution of ADAMTSL-4 in human iris, choroid and retina. in The British journal of ophthalmology

publication icon
Moustafa MT (2017) Protective Effects of Memantine on Hydroquinone-Treated Human Retinal Pigment Epithelium Cells and Human Retinal Müller Cells. in Journal of ocular pharmacology and therapeutics : the official journal of the Association for Ocular Pharmacology and Therapeutics

 
Description BIRAX
Geographic Reach Europe 
Policy Influence Type Membership of a guidance committee
 
Description Member of International Research Awards panle
Geographic Reach Europe 
Policy Influence Type Participation in a advisory committee
 
Description PhD Studentship
Amount £210,000 (GBP)
Organisation Santen Pharmaceutical Co., Ltd 
Sector Private
Country Japan
Start 09/2016 
End 03/2020
 
Description Project grant
Amount £69,704 (GBP)
Organisation Moorfields Eye Hospital NHS Foundation Trust 
Department The Special Trustees of Moorfields Eye Hospital General Fund
Sector Charity/Non Profit
Country United Kingdom
Start 01/2014 
End 03/2015
 
Description Project grant
Amount £75,000 (GBP)
Organisation Moorfields Eye Charity 
Sector Charity/Non Profit
Country United Kingdom
Start 03/2015 
End 11/2016
 
Description Studentship
Amount £100,000 (GBP)
Funding ID R180016A 
Organisation Moorfields Eye Charity 
Sector Charity/Non Profit
Country United Kingdom
Start 02/2019 
End 01/2022
 
Title Proteomics data from zebrafish retina 
Description Our data has been added to the ProteomeXchange to contribute to the full proteomics mapping of the zebrafish retina which is not yet complete. 
Type Of Material Database/Collection of data 
Year Produced 2016 
Provided To Others? Yes  
Impact The mass spectrometry proteomics data have been deposited in the ProteomeXchange Consortium database via the PRIDE partner repository 47 with the dataset identifier 
URL http://proteomecentral.proteomexchange.org
 
Description Endogenous retinal regeneration by stem cells 
Organisation Fudan University
Department Department of Ophthalmology
Country China 
Sector Academic/University 
PI Contribution Proteomic studies to identify candidate molecules that inhibit endogenous retina regeneration
Collaborator Contribution Testing candidate molecules for their potential to inhibit Muller stem cell growth and differentiation in vitro
Impact Poster presented at the meeting of the International Society for Ocular cell biology in Oxford, Sept 2013
Start Year 2013
 
Description Proteomics assays 
Organisation National Institute of Child Health (NICH)
Country Pakistan 
Sector Hospitals 
PI Contribution We performed proteomics analyses of human and zebrafish retina
Collaborator Contribution Provided equipment and knowledge of know how
Impact Paper in preparation for publication
Start Year 2013
 
Description Proteomics in zebrafish retina 
Organisation Moorfields Eye Hospital NHS Foundation Trust
Department NIHR Moorfields Biomedical Research Centre
Country United Kingdom 
Sector Academic/University 
PI Contribution Investigated proteomics profile in the zebrafish retina
Collaborator Contribution Provided methodology and analysis of tissue used for proteomics
Impact A paper is in preparation
Start Year 2013
 
Description Sourcing human retina tissue 
Organisation Moorfields Eye Hospital NHS Foundation Trust
Country United Kingdom 
Sector Public 
PI Contribution Investigated the proteomic profile of gliotic tissue
Collaborator Contribution Collaborator provided tissue from patients for research
Impact Paper publication
Start Year 2013
 
Description ARVO meeting 2015a (USA) 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Poster presentation and scientific discussions with other researchers
Year(s) Of Engagement Activity 2015
 
Description ARVO meeting 2015b (USA) 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Poster presentation and scientific discussions with other researchers
Year(s) Of Engagement Activity 2015
 
Description Dresden Conference 2016 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Poster presentation- Generated interesting discussion in the stem cell field
Year(s) Of Engagement Activity 2016
 
Description Eye Research conference 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Scientific presentation and discussions with other researchers
Year(s) Of Engagement Activity 2016
 
Description Eye Research conference (Poster presentation) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Poster presentation and scientific discussions with other researchers
Year(s) Of Engagement Activity 2016
 
Description Feature on visual disability 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact People becoming more aware of visual disability and prospects for future therapies

Have received emails from the public for information on my work
Year(s) Of Engagement Activity 2013
 
Description Invitation to speak at retina conference 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact I was invited to give a talk at a symposium organized by the German Foundation PRO RETINA. The meeting was attended by circa 400 Scientists, Young Research Fellows and Eye Charity members
Year(s) Of Engagement Activity 2016
 
Description Invited talk 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Postgraduate students
Results and Impact Circa 70 people attended talk, which generated much discussion with various individual groups on the day.
Year(s) Of Engagement Activity 2018
 
Description Invited talk 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Industry/Business
Results and Impact Circa 60 people attended the workshop which generated much discussion and informed Industry of new research developments on treatments for retinal diseases.
Year(s) Of Engagement Activity 2018
 
Description Invited talk at Eye research Conference 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Over 100 people attended talk at Workshop organized as part of an Eye conference. Talk generated important Scientific discussions.
Year(s) Of Engagement Activity 2018
 
Description Meeting of the Scientific and Medical Advisory Board of Retina International 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact Presentation generated important discussions with retina specialists

N/A
Year(s) Of Engagement Activity 2014
 
Description Patient symposium- Moorfields Eye Hospital 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Professional Practitioners
Results and Impact Patient- Clinical discussions to understand impact of eye disease
Year(s) Of Engagement Activity 2015
 
Description Scientific session moderator 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Invited to moderate Scientific session at International Eye conference. Moderated Scientific discussions amongst attendees.
Year(s) Of Engagement Activity 2018
 
Description Stem cell conference 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Discussions with Scientists an Clinicians on new developments on the application of stem cells to therapies.
Year(s) Of Engagement Activity 2016
 
Description Talk 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Policymakers/politicians
Results and Impact I was invited to a workshop organized by a charity to storm ideas and acquire current knowledge on new retinal therapies in order to define policy on their research funding scheme.
Year(s) Of Engagement Activity 2018
 
Description Talks with patient group 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Patients attending Glaucoma clinic at Moorefield's Eye Hospital were informed of current and prospective therapies available for their treatment.

Have received emails from patients asking further questions.
Year(s) Of Engagement Activity 2014
 
Description Worshop invitation 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Policymakers/politicians
Results and Impact Invitation to close workshop organized by the National Eye Institute of the United States in May 2016, as part of their Audacious Goal Initiative to cure blindness by 2020. The main purpose of the meeting was to discuss potential approaches for replacement of retinal ganglion cells from endogenous cell sources..
Year(s) Of Engagement Activity 2016
URL https://www.youtube.com/watch?v=U5pEcFPsOWU&feature=youtu.be