Stem Cell-Based Transplantation Approach Improves Vision in End-Stage Retinal-Degeneration Mice

In the Jan. 10 issue of the journal Stem Cell Reports, Dr. Michiko Mandai and colleagues at the RIKEN Center for Developmental Biology in Japan report that transplantation of induced pluripotent stem cell (iPSC)-derived retinal tissue improved vision in a mouse model of end-stage retinal degeneration.

3D observation of contact between host bipolar cells (green) and graft photoreceptors (red). Image credit: RIKEN.

3D observation of contact between host bipolar cells (green) and graft photoreceptors (red). Image credit: RIKEN.

End-stage retinal degeneration is a leading cause of irreversible vision loss and blindness in older individuals.

Patients with conditions such as retinitis pigmentosa and age-related macular degeneration lose vision as a result of damage to the outer nuclear layer of light-sensitive photoreceptor cells in the eye.

There is no cure for end-stage retinal degeneration, and currently available therapies are limited in their ability to stop the progression of vision loss.

One strategy to restore vision in patients who are blind from outer retinal degeneration is cell replacement.

Dr. Mandai and co-authors recently showed that stem cell-derived retinal tissues could develop to form structured outer nuclear layers consisting of mature photoreceptors when transplanted into animals with end-stage retinal degeneration.

But until now, it was not clear whether transplantation of these cells could restore visual function.

In the new study, the researchers set out to address that question. To do so, they first genetically reprogrammed skin cells taken from adult mice to an embryonic stem cell-like state, and then converted these iPSCs into retinal tissue.

When transplanted into a mouse model of end-stage retinal-degeneration, the iPSC-derived retinal tissue developed to form photoreceptors that established direct contact with neighboring cells in the retina.

Almost all of the transplanted retinas showed some response to light stimulation. The key to success was to use differentiated retinal tissue instead of retinal cells, which most researchers in the field use.

“Using this method was a key point. Transplanting retinal tissue instead of simply using photoreceptor cells allowed the development of more mature, organized morphology, which likely led to better responses to light,” Dr. Mandai said.

The team’s treatment strategy restored vision in nearly half of the mice with end-stage retinal degeneration.

When these mice were placed in a box consisting of two chambers that independently delivered electric shocks on the floor, they were able to use a light warning signal to avoid the shocks by moving into the other chamber.

“These results are a proof of concept for using iPSC-derived retinal tissue to treat retinal degeneration,” Dr. Mandai said.

“We are planning to proceed to clinical trials in humans after a few more necessary studies using human iPSC-derived retinal tissue in animals. Clinical trials are the only way to determine how many new connections are needed for a person to be able to see again.”

Although the results are promising, the authors caution that for now this therapy is at the developmental stage.

“We cannot expect to restore practical vision at the moment. We will start from seeing a simple light, then possibly move on to larger figures in the next stage,” Dr. Mandai said.