By growing human retinal tissue from stem cells, researchers have determined how the various types of cells that enable people to see colors develop. The new study sets the stage for the development of therapies and treatments for eye diseases like color blindness or macular degeneration.
What's more, the results - some of the first such vision research to be done on human tissue, versus that of mice or fish - further establish lab-grown organoids as a powerful model for studying mechanisms underlying human development.
Three types of cone photoreceptors are present in the retina, which respond to different wavelengths of light according to their pigments to give humans color vision. Mutations that affect the expression or function of these light-sensitive proteins are known to cause forms of color blindness and other eye diseases. According to the authors, however, little is known about how the specialized blue-opsin (short wavelength; S), green-opsin (medium wavelength; M), or red-opsin (long wavelength; L) cell subtypes develop in the human retina.
In the lab researchers grew stem cells into retinal tissue organoids that closely mirrored the developmental stages observed in in vivo retinal tissue. They found that blue-detecting cones developed first, followed by red- and green-detecting ones. In retinal organoids that lacked thyroid hormone receptor β (Thrβ), all cones developed into the S subtype. Thrβ binds with high affinity to triiodothyronine (T3), the more active form of TH, to regulate gene expression. Authors observed that addition of T3 early during development induced L/M fate in nearly all cones. Thus, TH signaling through Thrβ is necessary and sufficient to induce L/M cone fate and suppress S fate. TH exists largely in two states: thyroxine (T4), the most abundant circulating form of TH, and T3, which binds TH receptors with high affinity.
Authors found that deiodinase 3 (DIO3), an enzyme that degrades both T3 and T4, was expressed early in organoid and retina development. Conversely, deiodinase 2 (DIO2), an enzyme that converts T4 to active T3, as well as TH carriers and transporters, were expressed later in development. Temporally dynamic expression of TH-degrading and -activating proteins supports a model in which the retina itself controls TH levels, ensuring low TH signaling early to specify S cones and high TH signaling later in development to produce L/M cones.
Researchers note that their results provide insight into why pre-term infants with low levels of thyroid hormone often have a higher incidence of color vision defects.