Overview
Cell replacement therapy is an exciting idea that could become important way to treat blindness due to loss of the light-detecting cells in the eye (the ‘photoreceptor’ cells). For it to work, young photoreceptors need to move into the right place in the retina (the part of the eye that contains photoreceptors) where they can link up with other cells and start doing their job.
Unfortunately when photoreceptors are lost they can be replaced with scar tissue which forms a barrier that makes it hard for any new cells to move into position. The research team has found that fewer than 1 in 10 cells make it through when transplanted into animals with photoreceptor loss.
They have also found that low success rates are linked to high levels of molecules called ‘chondroitin sulphate proteoglycans’. And whenever they find low levels of these molecules, more transplanted cells succeed. So in this study the student will find out more about how these molecules are linked to cell transplant success.
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Scientific summary
Do chondroitin sulphate proteoglycans in the diseased retina impair transplanted photoreceptor
migration by inhibiting integrin signalling?Photoreceptor transplantation is a promising therapeutic strategy for the treatment of retinal degeneration. The team has previously shown that photoreceptors taken from a specific stage of their development can migrate into the recipient neural retina, differentiate into mature photoreceptors and restore visual function in a murine model of stationary night blindness. Importantly, they have described protocols for the generation of transplantable populations of donor photoreceptor precursors at an equivalent developmental stage from murine embryonic stem cells. Major challenges remain, however. The efficiency of donor cell integration remains low, encompassing just 10% of those transplanted and this is reduced further when transplanted into models of retinal disease.
For transplantation to be effective, large numbers of donor cells must migrate from the site of transplantation, through the inter-photoreceptor matrix (IPM), a region of the extracellular matrix (ECM) where the photoreceptor inner/outer segments reside, and into the recipient neural retina. Reactive gliosis occurs in the vast majority of retinal degenerations as a consequence of photoreceptor loss and the resulting glial scar that forms at the outer limits of the neural retina is a major barrier to efficient donor cell migration and integration.
The team has reported that high levels of chondroitin sulphate proteoglycans (CSPGs) produced during gliosis are correlated with poor transplantation outcome. In this studentship, they are testing the hypothesis that CSPGs prevent effective photoreceptor transplantation by impeding donor photoreceptor migration into the diseased retina. Moreover, they aim to determine whether this occurs via an integrin-dependent mechanism.