Cue Found that Switches Cell Role to Repair of Retinal Damage

One approach to harnessing stem cells for therapy, which researchers are investigating, is based on stimulating pre-existing stem cells in the body. Resident stem cells use cues from the tissues they reside in to determine which cell type to become. An advantage of this technique over injecting foreign stem cells into areas of damage is that the foreign cells may not turn into the cell type needed for repair.

Courtesy Dong Feng Chen

Second sight. Retinal progenitor cells differentiated into mature photoreceptor cells three weeks after aminoadipate treatment. Confocal images of retinal sections taken from an adult mouse at 21 days after aminoadipate treatment show (A) that proliferating progenitor cells (red, anti-BrdU) have migrated out of the inner nuclear layer (INL) to the outer nuclear layer (ONL) and (B and C) colocalize with immunostaining for the mature photoreceptor cell marker rhodopsin (green).

In the retina of the eye, Müller glial cells—non-neuronal cells that help maintain the health of retinal tissue—may be the key to repairing damage from retinal diseases that cause vision loss. These cells can turn into progenitor cells, similar to stem cells but more restricted in the cell types they engender. Until now, the signal that triggers the induction of a progenitor phenotype in Müller cells was unknown.

The laboratory of Dong Feng Chen, HMS assistant professor of ophthalmology at Schepens Eye Research Institute, determined that the glutamate neurotransmitter and its analog, aminoadipate, can transform Müller cells into progenitor cells that are capable of generating new retinal cells.

Injection of glutamate or aminoadipate into the back of the eye of adult mice caused Müller cells to divide and migrate out of the retinal layer where they normally dwell into the region where light-sensing photoreceptors reside. These proliferating cells expressed Müller cell markers and progenitor cell markers, confirming their identity. After several days, they differentiated into new photoreceptors that may be competent to heal damaged retinas.

When Müller cells were isolated from the retina and treated with glutamate or aminoadipate in culture, they turned into a broad range of retinal cells, suggesting that the retina provides environmental cues to progenitor cells that determine their ultimate cell type.

The use of aminoadipate was more efficient than glutamate at stimulating Müller cell growth because, unlike glutamate, it is specific for glial cells and does not bind to neurons. This makes the chemical an ideal candidate for therapeutic activation of retinal progenitor cells.

“This study is very significant,” said Chen. “It means it might be possible to use concentrated amounts of this chemical in a drug form to turn on the eye’s own resources to regenerate damaged retinas, without the need for transplanting outside retinal tissue or stem cells.”

The next step is to determine whether enough progenitor cells can be generated to restore retinal function in mice with retinal blinding disease.
The findings were published in the March edition of Investigative Ophthalmology and Visual Science.

—Kafi Meadows

Fetal Cell Grafts for Parkinson’s Thrive Long After Transplants

About 20 years ago, hopes ran high for treating Parkinson’s disease with fetal cell transplants to replace the dead dopamine neurons. Then came two disappointing double-blind, placebo-controlled trials, which were halted when symptoms of transplant recipients did not sufficiently improve or, in some cases, worsened.

Now, up to 16 years later, three studies report that transplanted cells grew and survived in eight people’s brains. And the grafted cells developed some of the namesake pigmentation characteristic of the dark dopamine cells in the substantia nigra that are the first casualties of Parkinson’s.

“I find it remarkable,” said Curt Freed of the University of Colorado Denver Health Sciences Center in an e-mail, “that all three reports and our experience in Colorado show that dopamine cell transplants survive and function.” Not an author on any of the papers, Freed and his colleagues are preparing a fourth study for publication that shows similar long-term evidence of brain repair in more transplant recipients.

The postmortem brains show that long-term brain repair with cell therapy may be possible, say authors of all three papers in the April 6 online Nature Medicine. The next generation of cell replacement studies for Parkinson’s will more likely use stem cells, rather than fetal brain tissue, and target younger people and those with less severe disease, based on data from the earlier clinical trials.

“Despite severe Parkinson’s pathology in the patients’ brains, the implanted dopamine neurons in the grafts look healthy, and they are growing into the host brain without evidence of disease,” said Ole Isacson, HMS professor of neurology at McLean Hospital, senior author of one of the studies. Isacson and his Canadian surgical colleagues evaluated the brains of two patients at nine years after transplant, one at 14 years posttransplant, and two more patients who died sooner of unrelated causes three to four years after transplant.

The two other study groups, however, did find alpha-synuclein in some grafts, plus tiny amounts of its potentially damaging aggregate. It is the protein associated with aging brains and with Parkinson’s in particular.

One study, reported by a Chicago and New York team, evaluated a woman who died 14 years after transplantation. “It is in the minority of cells,” said first author Jeffrey Kordower of Rush University Medical Center. “It should not change anyone’s opinion about whether or not stem cell or other cell replacement therapy should go forward.”

The other paper, from a Swedish team, saw similar alpha-synuclein–positive Lewy body–like pathologies in two people, who died 11 and 16 years posttransplant. Each patient had two grafts transplanted years apart, with the older tissues showing proportionally more of the protein and its aggregates. “It’s a rare event, and we have to look at many cells to spot it,” said senior author Patrik Brundin of Lund University in Sweden.

Further tests are needed to verify the identity, structure, and source of the Lewy bodies, said John Trojanowski of the University of Pennsylvania and co-author of the Isacson paper.

Meanwhile, neurons harvested from reprogrammed adult skin cells reduced symptoms in a Parkinson rat model, reported researchers in Isacson’s lab and colleagues in another paper the following day in the online Proceedings of the National Academy of Sciences.

—Carol Cruzan Morton

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