Synapse between transplanted cell (green) and host bipolar cell (red)

Introduction
Photoreceptor loss is the ultimate cause of irreversible blindness in many retinal diseases, varying from complex diseases such as AMD to single gene disorders like retinitis pigmentosa. Repair of such damage by cell transplantation may be able to reverse the blindness. In general, repair of the central nervous system by cell transplantation is a complex issue, requiring the cell to connect to the right downstream and upstream neuron. Replacement of photoreceptor cells by cell transplantation is one of the most feasible types of central nervous system repair; photoreceptor degeneration initially leaves the inner retinal circuitry intact and new photoreceptors need only make single, short synaptic connections to contribute to the retinotopic map. So far, brain- and retina-derived stem cells transplanted into adult retina have shown little evidence of being able to integrate into the outer nuclear layer and differentiate into new photoreceptors. Furthermore, there has been no demonstration that transplanted cells form functional synaptic connections with other neurons in the recipient retina or restore visual function. This might be because the mature mammalian retina lacks the ability to accept and incorporate stem cells or to promote photoreceptor differentiation.

We decided that a systematic approach to the development of successful stem cell therapy for photoreceptor cell loss requires two stages. Firstly, suitable stem cells need to be identified and cultured; a method of differentiation of these stem cells to the correct cell type prior to implantation needs to be established. Secondly, a protocol for the transplantation of the stem cells needs to be developed, allowing the implantation of the cells in the retina and the formation of synaptic connections.


Retinal repair by transplantation of photoreceptor precursors

Isolation, culture and differentiation of adult stem cells

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