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

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 from the Natural Science Foundation of China.

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.

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.