Improving longevity of functionally integrated stem cells in regenerative vision therapy

January 12, 2017
Image showing transplanted GFP-expressing human stem cell derived photoreceptors integrated in a host rodent retina stained for Otx2 in red. Credit: Jie Zhu, Buck Institute for Research on Aging

Stem cell therapies hold great promise for restoring function in a variety of degenerative conditions, but one of the logistical hurdles is how to ensure the cells survive in the body long enough to work. Researchers from the Buck Institute report one of the first demonstrations of long-term vision restoration in blind mice by transplanting photoreceptors derived from human stem cells and blocking the immune response that causes transplanted cells to be rejected by the recipient.

Publishing in the Cell Stem Cell, this work highlights immune system rejection as one of the key issues that needs to be addressed to improve efficiency of therapies. The findings support a path to improving clinical applications, specifically for restoring vision in humans by allowing photoreceptors derived from human to integrate and thrive in the eye.

"This turned into a nice story of long-term restoration of vision in completely blind mice," said Buck faculty and senior author Deepak Lamba, PhD, MBBS. "We show that these mice can now perceive light as far out as 9-months following injection of these cells."

Photoreceptors are specialized neurons in the retina that convert light into signals that the brain interprets as sight. Loss of these cells is a common endpoint in . Human can provide a potential source for photoreceptor replacement, but despite Lamba's prior work showing that photoreceptors derived from stem cells could function in mice, researchers hadn't been able to show long-term sustained vision restoration. A major controversy in field, said Lamba, was whether the transplanted photoreceptors simply die off or were being actively rejected by the immune system - the eye, along with the brain, had long been thought to be "privileged" in that the cells of the immune system didn't monitor those locations.

Lamba's group set out to examine in detail the degree to which immune rejection contributes to disappointing outcomes in for the eye, and to determine if they could find a way around the problem. If rejection was occurring and that could be suppressed, they reasoned, transplanted photoreceptors derived from stem cells might have time to integrate into the visual system and start relaying information to the brain.

The team used a specific mouse strain that is healthy but it is lacking in a specific immune cell receptor, which makes the mouse unable to reject transplanted foreign cells. Called immunodeficient IL2 receptor gamma (IL2rγ) null mice, these animals lack the IL2rγ receptor that humans also have as part of a functional immune system.

"This mouse strain is great model for this research because they are otherwise healthy and normal, including in their vision, so it allows us to conduct studies focused on cell integration," said the publication's lead author, Jie Zhu, PhD, a postdoctoral researcher who started in Lamba's lab three years ago.

In these mice, the team showed that without the rejection process, there was a 10-fold increase of living human embryonic stem cell-derived donor retinal cells that matured and integrated into the retina.

After seeing significantly improved long-term survival and integration of the , the next step was to see if the cells actually functioned. The team transplanted stem cell-derived into another strain of mouse, called CRX null, which is congenitally blind. The team measured the pupils' response to light and examined the brains' visual response centers to show that signals from the eye were going to the appropriate areas of the brain. They found that even nine months to a year after photoreceptor transplantation, eyes were responding to light and transmitting sight messages to the brain.

"That finding gives us a lot of hope for patients, that we can create some sort of advantage for these stem cell therapies so it won't be just a transient response when these cells are put in, but a sustained vision for a long time," said Lamba. "Even though the retina is often considered to be 'immune privileged,' we have found that we can't ignore cell rejection when trying to transplant stem cells into the eye."

Dr. Lamba's lab is dedicated to the clinical applications of human stem cells, with a special interest in restoring vision that has been compromised by degenerative eye diseases, such as macular degeneration. They are already refining the current work, said Zhu and Lamba. One direction is to use drugs already approved to prevent rejection for organ transplant that target the same IL2? receptor. "Using an antibody against this specific receptor means that the might not need to be suppressed more generally, which can be very toxic," said Zhu.

"We can also potentially identify other small molecules or recombinant proteins to reduce this interleukin 2 receptor gamma activity in the body - even eye-specific immune responses - that might reduce cell rejection," said Lamba. "Of course it is not validated yet, but now that we have a target, that is the future of how we can apply this work to humans."

Explore further: Stem cell therapy reverses blindness in animals with end-stage retinal degeneration

More information: Immunosuppression via loss of IL2r? enhances long-term functional integration of hESC-derived photoreceptors in the mouse retina, Cell Stem Cell, DOI: 10.1016/j.stem.2016.11.0193

Related Stories

Stem cell therapy reverses blindness in animals with end-stage retinal degeneration

January 10, 2017
A stem cell-based transplantation approach that restores vision in blind mice moves closer to being tested in patients with end-stage retinal degeneration, according to a study published January 10 in Stem Cell Reports. The ...

Harnessing an innate repair mechanism enhances the success of retinal transplantation

June 30, 2016
Regenerative therapies, based on cell replacement, hold promise for a wide range of age-related diseases, but efforts to bring the therapies to patients have not been very successful - in large part because the newly-derived ...

Krembil research prompts rethink on established vision recovery theory

December 14, 2016
A team of researchers at the Krembil Research Institute has published a paper that is expected to change the way scientists think about vision recovery after retinal cell transplantation.

Stem cells transplanted in monkeys without anti-rejection drugs

September 15, 2016
Scientists report they have successfully transplanted reprogrammed monkey stem cells into the eyes of other monkeys without the need for anti-rejection drugs.

Study provides hope for some human stem cell therapies

August 20, 2015
An international team of scientists headed by biologists at UC San Diego has discovered that an important class of stem cells known as human "induced pluripotent stem cells," or iPSCs, which are derived from an individual's ...

A new mode of communication between donor and host photoreceptors in retinal dystrophy

October 24, 2016
UK eye researchers with funding from Fight for Sight have discovered a new means of communication between transplanted donor photoreceptors developed from stem cells and the degenerating photoreceptors of the host retina. ...

Recommended for you

Drug found that induces apoptosis in myofibroblasts reducing fibrosis in scleroderma

December 15, 2017
(Medical Xpress)—An international team of researchers has found that the drug navitoclax can induce apoptosis (self-destruction) in myofibroblasts in mice, reducing the spread of fibrosis in scleroderma. In their paper ...

How defeating THOR could bring a hammer down on cancer

December 14, 2017
It turns out Thor, the Norse god of thunder and the Marvel superhero, has special powers when it comes to cancer too.

Researchers track muscle stem cell dynamics in response to injury and aging

December 14, 2017
A new study led by researchers at Sanford Burnham Prebys Medical Discovery Institute (SBP) describes the biology behind why muscle stem cells respond differently to aging or injury. The findings, published in Cell Stem Cell, ...

'Human chronobiome' study informs timing of drug delivery, precision medicine approaches

December 13, 2017
Symptoms and efficacy of medications—and indeed, many aspects of the human body itself—vary by time of day. Physicians tell patients to take their statins at bedtime because the related liver enzymes are more active during ...

Time of day affects severity of autoimmune disease

December 12, 2017
Insights into how the body clock and time of day influence immune responses are revealed today in a study published in leading international journal Nature Communications. Understanding the effect of the interplay between ...

Estrogen discovery could shed new light on fertility problems

December 12, 2017
Estrogen produced in the brain is necessary for ovulation in monkeys, according to researchers at the University of Wisconsin-Madison who have upended the traditional understanding of the hormonal cascade that leads to release ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.