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Retinal Stem Cells and Eye of Newt

Cultured human RPE cells look like cobblestones, and 3% of them act like  stem cells — in dishes. Could they treat eye diseases? (Tim Blenkinsop)

More than a decade before Sally Temple, PhD, and her husband Jeffrey Stern, MD, PhD, discovered stem cells in human eyes, they suspected the cells would be there. They knew it from the salamanders.

When William Shakespeare included “eye of newt” in the Three Witches’ brew in Macbeth, he probably knew what he was doing. Dr. Temple, who grew up in northern England, said it’s long been common knowledge there that newts can regrow their parts. In the late 1800s, biologists began to study regeneration in salamanders.

By the 1950s, embryologists had discovered that certain amphibian eyes regenerate thanks to a single layer of cells, called the retinal pigment epithelium (RPE), which hugs the photoreceptors (the rods and cones). The RPE is the source of the new stem cells — RPESCs — that are housed in a spectacular building overlooking the Hudson River in Rensselaer, New York. Here, Drs. Temple and Stern and their two dozen associates form the Neural Stem Cell Institute/Regenerative Research Foundation.

Amphibians became an essential part of  developmental biology. In my lab in grad school at Indiana University, when we’d tire of counting flies, we’d fish out newly-fertilized eggs from the tank of Sally (not Temple) and Gerry. They were our pet axolotls, rescued from the salamander colony upstairs. I loved watching the cells cleave, forming soccer-ball-like early embryos right before our eyes.

Sir John Gurdon’s experiments with amphibians paved the way for today’s stem cell research. (Wellcome Library)

Some of the earliest “nuclear transplantation” (aka cloning) experiments in animals used amphibians, starting in the 1950s. And some of the most elegant experiments in biology were those of Sir John Gurdon, who shared the Nobel Prize in Physiology or Medicine in 2012 with Shinya Yamanaka (of more recent induced pluripotent stem cell [iPS]) fame).

Dr. Gurdon cloned adult Xenopus laevis frogs from tadpole cells, a species once noted for use in a pregnancy test for people. And he was one of Dr. Temple’s professors at Cambridge, where she did her undergraduate work, “not realizing I was in a hotbed of developmental biology,” she recalled.

With this legacy, by the time Dolly the cloned sheep hit the headlines in 1996 and people panicked at the specter of mass-produced Nazis and dinosaurs, developmental biologists wondered, what took so long?

If only we could regrow parts like salamanders (and cockroaches) can. (Larry Lewis)

Among the amphibians, salamanders are especially adept at regenerating their eyes, which have a layered structure similar to our own. “If they have retinal damage, or you remove the retina, the RPE is activated. It’s cells divide, differentiate, and make a new retina,” said Dr. Temple. That’s a classic description of a stem cell. “We knew these cells could behave like stem cells and regenerate the retina. It’s locked inside the cells and if we can figure out how to unlock it, we can make not just RPE, but photoreceptors.” She paused a moment. “Regeneration is THE question in science and medicine, isn’t it?”

The RPE is an oft-underappreciated cell type, in a similar situation to the neuroglia that keep neurons alive. Like Anne Hathaway’s “supporting” but critical role in Les Miserables, the thin RPE is essential for the functioning of the intricately folded, majestic rods and cones. We need RPE to see. The importance of the RPE makes it all the most astonishing that it forms when we’re one-month-old embryos and stays put, its cells never dividing unless something goes wrong.

“We have embryonic cells in our eyes, but they’re not embryonic stem or pluripotent cells. They’re restricted to making a few cell types,” Dr. Temple said as she sketched cells, something that developmental biology lends itself to and that she does when talking about her work.

The researchers obtained human RPEs from eye banks that harvest corneas and then discard what’s left. In a body, RPE cells are quiescent, but in culture they divide like crazy, forming coatings of cobblestone-like cells festooned with RPE markers.

To show that an RPE cell could be a stem cell, the researchers gently removed one at a time and transferred it to its own dish, giving it space to divide. This would reveal the defining characteristic of a stem cell: the ability to self-renew, to copy itself. (If all a stem cell could do was “turn into any cell type,” as they’re often defined, the culture would soon poop out. I see this oversimplification in news releases and media reports on a near-daily basis.)

Most of the rehomed RPE cells promptly perished, but about 3% of them self-renewed and yielded RPE cells. Dr. Temple estimates, from watching this happen, that one original isolated RPE cell with this hidden talent could generate a thousand RPE cells.

A few weeks ago, Tim Blenkinsop, PhD, showed me a plate of RPE cells at the Neural Stem Cell Institute. They all looked the same under the microscope. Was I missing something? “We don’t know which are which. The stem cells self-renew. Remove one and it can re-establish a monolayer. But there are no pure cultures of RPE-SC,“ he explained.

Sally Temple, PhD

Dr. Temple continued. “This is a tissue that wasn’t previously understood to have a stem cell line. It isn’t a proliferative tissue, but hidden within it is this population of cells that can be activated to divide.” Because the RPE yields stem cells in a dish, they probably can in an eyeball, and perhaps do so in response to injury or illness.

Dr. Jeffrey Stern, MD, PhD

Drs. Stern and Temple see their cells as “another horse in the race,” alongside human embryonic stem cells, which are providing RPE to treat Stargardt’s macular dystrophy and macular degeneration. Another approach is to generate RPE from iPS cells. At the Neural Stem Cell Institute, Barb Corneo, PhD, and her husband, Dr. Blenkinsop, are “the keepers of the cells,” including iPS cells.

“The iPS-cell-derived RPE stem cells are more pigmented,” Dr. Corneo said “and the adult ones are lighter” added Dr. Blenkinsop, in that complete-each-other’s-sentences way I’ve encountered before in spouses who share science. The adult-derived ones dilute their pigment when they divide.

To observe the cells I wore a blue lab coat and purple gloves so I didn’t sicken them. Dr. Corneo slid a culture dish harboring cells from various eye parts under the microscope. “We use these as donors to make iPS cells,” she said, replacing the dish with a 6-welled container. “These are just plain iPS cells, the island among the feeder cells,” she explained.

Like a coffee lover seeing a Starbucks sign, I recognized the iPS cells instantly, having seen them in so many images since their invention in late 2007. It was as thrilling as watching salamander embryo cells cleave.

“Those cells can make anything. Barb just pushes them down the pathway to make RPE,” Dr. Temple explained.

The RPESCs are of intense interest because of what they can become. When the researchers exposed RPE cells in culture to a cocktail of factors promoting specialization as neurons, the cells become marked with molecules characteristic of nerve cells – suggesting that Dr. Temple’s dream of regenerating photoreceptors may be possible.

The goal is to use the cells to treat eye diseases. And they seem perfect. “Embryonic stem cells very rapidly form RPE by default. RPE is one of the first tissues to terminally differentiate in normal development, so in a way our cell is an intermediate cell. Rather than control the early steps, which we don’t really understand, why don’t we start later, closer to our target tissue? Rather than a pluripotent cell that can do everything, we have a stem cell that can do what we want. It’s nature’s specialist,” explained Dr. Stern, an ophthalmologist.

Age-related macular degeneration destroys the rods and cones in the central retina first. (Natl Eye Institute)

Many of Dr. Stern’s patients have age-related macular degeneration (AMD), as do 12-15 million people in the U.S. and 25% of people over 60. Central vision fades as rods and cones die. Ten percent of cases are “wet,” in which blood vessels in the eye overextend and leak in response to the RPE forming scar tissue. The RPESCs would treat dry AMD, possibly replacing relocation of part of a patient’s RPE to patch blurry spots, according to Pete Coffey, PhD, professor of cellular therapy and visual sciences at the UCL Institute of Ophthalmology. 

“In an ideal world we could take some of these RPE cells from a patient and grow them up. To treat AMD we’d only need 30,000 to 50,000 cells to cover the part that’s degenerated. We want to access the salamander potential for a short period to repair the RPE or the retina,” Dr. Temple said. The cells can also be used as a “disease in a dish” to test drugs.

The stem cell characteristic that frightens critics is what entices many researchers: discovering new fates. The RPESC can be coaxed to give rise to what Dr. Temple calls “bizarre mesenchymal things” – bone, cartilage, and fat.

The two fates – RPE and mesenchyme – hail from different layers of the earliest embryo, the ectoderm and mesoderm, respectively. Practically speaking, the ability of the eye to produce bone, cartilage, and fat explains two strange diseases.

Proliferative vitrioretinopathy (PVR) and phthisis bulbi (“macular pucker”) are medical emergencies. “The RPE moves, proliferates, and makes fibers that pull the retina off. No one had shown previously that RPE could make mesenchymal cells, so when we discovered this potential, ophthalmologists became excited because maybe we could prevent these diseases,” Dr. Temple explained. “In some awful situations, the retina can calcify – where does the bone come from? Maybe from misbehaving RPE.”

So the RPESCs may have a dual use. “One cell under some circumstances can make healthy RPE that can be used in replacement therapy, and in another set of circumstances can push into an abnormal mesenchymal fate that can be a model to screen drugs for PVR and macular pucker,” Dr. Temple said.

I normally wouldn’t write about work published a year ago that’s already been covered quite well, but I have a few updates, ranging from the profound to the personal.

1. December 12, 2012 was an important date for two reasons. The Empire State Stem Cell Board and the New York State Stem Cell Program recommended the Regenerative Research Foundation, the not-for-profit arm of the Rensselaer facility, for a $10.6 million grant. “Our tiny institute got the top score! We were astonished,” said Dr. Temple. The Neural Stem cell Institute formed the Retinal Stem Cell Consortium to bring others in to do some of the preclinical work.

The same day, the National Academy of Sciences released conclusions of a year-long investigation of the progress of the California Institute of Regenerative Medicine, critical of the $6 billion program to fund stem cell research that began in 2004 after voters approved Proposition 71.

The daughters of neural stem cells are easier to see than RPE, using stains. The green cells are astrocytes, the red cell a neuron, and the orange cell hasn’t yet made up its mind which developmental pathway to follow. (Credit: Eric Laywell)

2. The RPESC seem to be an entirely new class of stem cells because there isn’t a stain that makes them stand out, as can the better-studied neural stem cells in our brains . (These cells were found in rodent brains in 1912; then in birds, who use them to learn songs; then in tree shrews and marmosets; and finally in tongue cancer patients who donated their brains. The strange story is in my little-known book “Discovery: Windows on the Life Sciences.”)

3. While I’m glad that the bioethics community seems to have left embryos to tackle stem cell tourism , the embryo issue resurfaced during the Presidential election. It’s nice to know that many researchers are forging ahead with the pools of potential right in our bodies – sometimes hidden in plain sight.

Gene therapy is optimal when cells are still healthy, as they were for Corey Haas. Stem cells may find a niche when disease has progressed to destroy cells. (Credit: Wendy Josephs)

4. Finally, and more philosophically, is the irony of RPE cells that reinvent themselves as stem cells. Their existence counters the premise of my book ““The Forever Fix: Gene Therapy and the Boy Who Saved It.”

The book’s star, Corey Haas, had a “forever fix” of his inherited blindness when billions of viruses injected into his eyes delivered replacement genes – days later he saw the sun for the first time, at the Philadelphia zoo. Corey is unlikely to need another gene therapy, precisely because his doctored RPE cells are not expected to ever divide, which would dilute the fix. Could RPESCs naturally nestled within his eyes have been reawakened to heal from within, given the right signals?

This is what I love about science: the enigmas and the inconsistencies, the disappointments that turn into detours, the unexpected findings that fuel discovery. That’s why there’s no such thing as “scientific proof,” despite what advertisers pitch to the public. New observations and unanticipated results continually alter what we thought we knew – and entice us to think harder and ask different questions about how nature works.

  1. I am from Australia. I have been diagnoised generally with a retinal eye disorder. Currently, I am undertaking my higher degree studies at the Australian National University. Using supporting equipments in my study, it is taking me snail’s pace to do my studies. I am therefore quite interested in your method of treatment if that can help me improve my vision.

    I look forward to hearing from you soon.

    Yours sincerely

    Kwalimu Virobo

  2. Chozin,

    Send me an email to iarons(at) and I’ll be happy to send you by return email, my table that lists all of the clinical trials currently underway using stem cells to treat retinal diseases.

    Irv Arons

  3. Irv Arons

    I am writing on behalf of my husband who lost sight cause by a bad car accident. Thank you that you are helping me answer my question. I received an email from stem cell transplant place in UK this morning saying that stem cell treatment can’t make a blind man see again if it is cause by accident. Thank u.

  4. Thanks, Irv, I agree completely. Offering a stem cell treatment that has not undergone rigorous clinical trial testing is termed “stem cell tourism” among bioethicists. You can look at to see trials that are recruiting patients. I was recently in Las Vegas and someone tried to sell my friend a stem-cell based anti-wrinkle cream for $1500! When I tried to photograph the product he grabbed my phone!

  5. Hi Ricki!
    I googled “RPE cell retinal” so I could get the full name of the RPE acronym for the article I’m writing and it led me to this fantastic article your wrote. With a magnified screen, I didn’t see the author but as I went along, I knew it had to be you. Who would have thought that every time I hop on the Amtrak train at the Albany-Rensselaer station that I was right under the nose of some interesting RPE cells!

  6. What an impressive essay this is!! Please follow with today’s newest clinical trials which are now in progress!! Thanks for sending this to the public!!

  7. My daughter has just been diagnosed with retinoschisis and has been exploring
    all the newest methods for addressing problems of her retinal degeneration. Turtles are her favorites, but I know she will switch to salamanders, thanks to Drs. Stern & Temple!

  8. I have looked into different places that offer stem cells for eyes. Some of these use stem cells from bone morrow and some say they use stem cells from your own fat. Can you tell me where they are doing clinical trials that are real.

  9. lists approved clinical trials. But, I just discovered yesterday that some companies charge patients to enroll in clinical trials. I do not think they are supposed to do that. A lot of the work is still preclinical — in non human animals.

    Mesenchymal stem cells are very useful and can come from a variety of sources.

  10. I paid $20000 for my bone marrow stem cells by MD stem cells in Fort Lauderdale but I didn’t receive any benefit. They are on Stem cells .org, they are the SCOTS Therepy people.

  11. I’m not sure of the legitimacy of this comment. I’m also scheduled for the same treatment, but it’s not MD Stem Cells who performs the procedure. They’re in an entirely different state, are merely the contacts for the clinical trial, NCT01920867.

    Perhaps this person could validate by stating when exactly the treatment occurred (i.e. what date) and elaborate more on their situation.

  12. Thank you for sending me this article and also for the comment from Dee on stem cells through the SCOTS Trial. I also looked into this. I also have the dry form of macula degeneration. I wondered if any one had been helped with this. That answered my question. When a person can’t see well, they are willing to do anything to get better eye sight, but there are so many scams out there.

  13. There is currently a clinical trial underway, using RPE derived from hESC type stem cells that is showing promise. One patient went from 20/400 vision to 20/40! See my post above on how to contact me for information about that clinical trial.

  14. Dr Levy has a huge artical about a new process of stem cell therapy for dry AMD, but after paying $20000 with no result I might wait until something more positive happens. Despite the SCOTTS clinical trial being offered, it still costs $20000 because no company or government will sponsor the trial. I like the prospect of a few treatments in the pipeline, one is the contact lense soaked in stem cells, another is the ‘patch’ soaked in stem cells and placed behind the retina so that the cells don’t migrate somewhere else,I also like the new lens that can give 2x magnified vision giving superior eye site, non invasive so hopefully trials will be short.

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