A paper published yesterday in the Proceedings of the National Academy of Sciences describes the generation of retinal progenitor cells from human embryonic stem (ES) cells. The work could potentially lead to new treatments for inherited retinal diseases such as macular degeneration and retinitis pigmentosa, in which photoreceptors and other retinal cell types degenerate.
Lamba, et al, show that human ES cells differentiate into retinal progenitors and, when co-cultured with other retinal cells, form synaptic connections with them. Furthermore, upon transplantation into live animals, the ES cells migrated into the layers of the retina, where 80% of them differentiated into retinal progenitors and then into inner retinal cells (amacrine and ganglion cells).
The newly-generated cells (A, left) were morphologically similar to retinal neurons derived from foetal retinae (B, left); immunohistochemistry was used to determine that they expressed markers of retinal cell types. A small number of the cells differentiated into rods and cones, the light-sensitive cells in the retina, and expressed photopigments.
Although the cells also expressed functional glutamate receptors, the extent to which they became integrated into the circuitry of the retina is unclear. The group is currently repeating the experiments to see if ES cell-derived retinal neurons can restore vision in blind animals.
Advanced Cell Technology (ACT), a biotechnology company based in Alameda, California, is also using stem cells to generate retinal neurons. The company’s researchers have developed a method to make ES cells differentiate into pigment epithelial cells, another retinal cell type which is lost in macular degeneration. ACT is planning to apply to the U.S. Food and Drug Administration (FDA) for permission to start human clinical trials.
Before this research can lead to any potential sight-restoring therapies, researchers must first find a way to induce the differentiation of greater numbers of photoreceptors. Transplantation of ES cells that have already been induced to differentiate into rods or cones would overcome this, but it is unclear whether transplanting differentiated cells is better than transplanting pluripotent cells which then differentiate in vivo. Although the ability to induce ES cells to differentiate into retinal neurons is a big achievement, researchers must now find a way to make those cells form stable, functional connections with other cells in the retina upon transplantation.
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Structure of the retina
The retina is a layered structure at the back of the vertebrate eye; some cephalopods also have retinae. During neural development, the retina and optic nerve originate as an outgrowth of the brain, and both structures are therefore considered to be part of the central nervous system.
This drawing by Santiago Ramony Cajal shows the layers and cell types in the retina and their connections. (A – Layer of rods and cones (photoreceptors); B – visual cell body layer; C – outer plexiform layer; D – bipolar cell layer; E – inner plexiform layer; F – ganglion cell layer; and G – optic nerve fibre layer.)
- Photoreceptors
- The rods and cones are photoreceptors; these cells contain pigments and are sensitive to light, in response to which action potentials are generated and transmitted to other retinal cells.
Cones contain 3 types of photopigments, called rhodopsins, which are sensitive to different wavelengths of light; cones are involved in colour vision. On the other hand, rods contain only one type of photopigment and are therefore only used for night vision. A rod is sensitive enough to respond to a single photon of light.
The 3 photopigments present in cones confer trichromatic vision. The wavelengths of visible light to which the 3 types of cones have peak sensitivity are 440, 544 and 580 nanometres, corresponding to blue, green and red light respectively. The combined activation of the 3 types of cones to differing extents enables perception of all the colours in the visible light spectrum.
Phototransduction
Phototransduction is the process by which light, in the form of photons, is converted into electrical impulses. This takes place in the rods and cones. The layer containing rods and cones is found at the back of the retina, so that light entering the eye has to pass the other cell layers before photons activate the rods and cones.
At rest, there is a steady of positively-charged sodium ions into photoreceptor cells. This so-called ‘dark current’ keeps the cell membrane depolarized at about -40mV, so that it releases inhibitory neurotransmitters.
Absorption of a photon by a rod or cone cell causes a conformational change in rhodopsin structure, which initiates a complex biochemical pathway, whose ultimate result is a hyperpolarization of the cell. This hyperpolarization reduces the release of inhibitory transmitters, so that action potentials are generated in the bipolar cells. This in turn causes activation of the ganglion cells, whose axons leave the retina to form the optic nerve.
Mo Costandi 
