Stem Cell Advance Brings Vision Repair in Sight

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Transplantation of cones produced from stem cells could reverse macular degeneration. A new differentiation approach yields abundant cones from human embryonic stem cells. When allowed to grow to confluence, the cones spontaneously form sheets of organized retinal tissue. [G. Bernier, University of Montreal]
Transplantation of cones produced from stem cells could reverse macular degeneration. A new differentiation approach yields abundant cones from human embryonic stem cells. When allowed to grow to confluence, the cones spontaneously form sheets of organized retinal tissue. [G. Bernier, University of Montreal]

A dearth of cone cells means degraded vision, so perhaps cone cell numbers could be raised, if only there were a way to produce cone cells in abundance. Then, cone cells could be transplanted en masse, potentially reversing the vision losses due to age-related macular degeneration.

We are born with a fixed number of cone cells. Additional cone cells must be contrived if degradation of the retina, a condition that is accelerated in nearly one out of four people, is to be reversed. Although cone cells have been produced by means of stem cell differentiation, the output has been meager. Now, however, scientists at the University of Montreal report that they have developed an efficient technique for producing cone cells from human embryonic stem cells.

These scientists, led by Gilbert Bernier, Ph.D., essentially closed a number of signaling pathways in stem cells, leaving open a default pathway that led to photoreceptor genesis. The scientists detailed their work in the journal Development, in an article that appeared online October 1. The article—“Differentiation of human embryonic stem cells into cone photoreceptors through simultaneous inhibition of BMP, TGFβ, and Wnt signaling”—is the culmination of years of work.

Bernier has been interested in the genes that code and enable the induction of the retina during embryonic development since completing his doctorate in molecular biology in 1997. “During my post-doc at the Max-Planck Institute in Germany, I developed the idea that there was a natural molecule that must exist and be capable of forcing embryonic stem cells into becoming cones,” he said. Indeed, bioinformatic analysis led him to predict the existence of a mysterious protein: COCO, a “recombinational” human molecule that is normally expressed within photoreceptors during their development.

In 2001, Bernier launched his laboratory in Montreal and immediately isolated the molecule. But it took several years of research to demystify the molecular pathways involved in the photoreceptors development mechanism. The Bernier laboratory’s current work has established that Coco (Dand5), a member of the Cerberus gene family, is expressed in the developing and adult mouse retina.

“Upon exposure to recombinant COCO, human embryonic stem cells (hESCs) differentiated into S-cone photoreceptors, developed an inner segment-like protrusion, and could degrade cGMP when exposed to light,” Bernier and colleagues wrote in the Development article. “Addition of thyroid hormone resulted in a transition from a unique S-cone population toward a mixed M/S-cone population.”

In addition, when the COCO-exposed hESCs were cultured at confluence for a prolonged period of time, they spontaneously developed into a cellular sheet composed of polarized cone photoreceptors. “Within 45 days, the cones that we allowed to grow toward confluence spontaneously formed organized retinal tissue that was 150 microns thick,” Dr. Bernier noted. “This has never been achieved before.”

In order to verify the technique, Dr. Bernier injected clusters of retinal cells into the eyes of healthy mice. The transplanted photoreceptors migrated naturally within the retina of their host.

Although Dr. Bernier acknowledged that the transplantation of photoreceptors in clinical trials was years away, he expressed optimism that his laboratory had made a significant advance, one that could, ultimately, benefit countless patients. “Our method has the capacity to differentiate 80% of the stem cells into pure cones,” Dr. Gilbert explained. “Thanks to our simple and effective approach, any laboratory in the world will now be able to create masses of photoreceptors.”

Beyond the clinical applications, Dr. Bernier's findings could enable the modeling of human retinal degenerative diseases through the use of induced pluripotent stem cells, offering the possibility of directly testing potential avenues for therapy on the patient's own tissues. “Our work,” the Development article concluded, “provides a unique platform to produce human cones for developmental, biochemical, and therapeutic studies.”








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