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One stem cell or many?

Yale Medicine Magazine, 2016 - Spring


Scientists track a cell behind Parkinson’s disease.

Parkinson’s disease once looked like a poster child for stem cell therapy. Researchers knew that the chronic illness started when cells that produced the neurotransmitter dopamine died. Without dopamine, such symptoms as muscle rigidity and tremors emerged. As early as 1990, a team in Sweden transplanted dopamine-producing cells from human fetuses into the brain of a male Parkinson’s patient. Two months later, the patient’s right arm appeared less rigid, and he could sleep through the night, the researchers wrote in the journal Science. Transplanted brain cells, the trial showed, could reverse some of Parkinson’s hallmarks. Two more decades would pass before scientists found clues to suggest why the therapy worked. In the meantime, a reliable cell-based therapy for Parkinson’s remains out of reach.

When D. Eugene Redmond Jr., M.D., professor of psychiatry and of neurosurgery, began researching Parkinson’s in the 1980s, patients had only one main treatment option: a pill called levodopa, or l-dopa, which the brain converts to dopamine. The drawback? While effective early on, the drug eventually stops working, and can cause awful side effects like hallucinations. If a fresh supply of neuronal stem cells began replacing dopamine in a tiny midsection area of the brain, the symptoms could be eliminated and the disease could be considered cured, Redmond said.

Thirty-five years ago, Redmond started his lab on the Caribbean island of St. Kitts. Overrun with vervet monkeys, the island provided Redmond access to primates that can develop Parkinson’s symptoms in ways that closely mimic symptoms in humans. The disease can be induced in monkeys by exposing them to the synthetic drug MPTP, a neurotoxin. It kills the dopamine-producing neuronal cells in the brain—humans exposed to the drug also develop Parkinson’s symptoms. In 1985, Redmond injected fetal dopamine neurons directly into the monkeys’ brains and they improved. This evidence helped support clinical trials in humans that would come later, including the Swedish study. Those neuronal cells, however, could not be grown in vitro, and the use of fetal tissue was and still is controversial.

Redmond and his lab members then tried multiple types of stem cells to see which could work as well as the fetal tissue grafts. Recently, they tried induced pluripotent stem (iPS) cells. These cells, derived from a monkey’s skin cell, can be reprogrammed to become stem cells, then turned into dopamine neurons and injected back into the same monkey. Researchers want to use iPS cells as therapy in humans because the body is less likely to reject what it recognizes as its own tissue.

Some monkeys that received iPS cells got better, but not predictably or consistently. Redmond and colleagues wondered whether they’d missed a piece of the puzzle: Were they putting in the right type of dopamine neuron—the cell that they had been transplanting over the years? Or perhaps the transplanted cells were not receiving the correct signals—called growth factors—from surrounding cells.

Genetic sequencing technology could help answer these questions. Historically, A9 dopaminergic neurons, the ones predominantly lost in Parkinson’s disease, have been grouped into a single cell class, said Montrell Demond Seay, Ph.D., associate research scientist in psychiatry, who works in Redmond’s lab. “If your transplanted neuronal stem cell is not the one doing the real functional heavy lifting, then your replacement therapy will never work,” Seay said. With the help of Sherman Weissman, M.D., Sterling Professor of Genetics, and Jennifer Yang, M.D., Ph.D., associate research scientist in genetics, Seay has sequenced about 200 neuronal stem cells from a single monkey. They extracted RNA from the A9 dopaminergic neurons and sent the material off for genetic sequencing. Next, a biostatistician will determine whether there are different A9 neuron cell types. Seay’s goal is to sequence 1,000 neurons from five different monkeys. Seay hypothesizes that each A9 cell subtype is linked to a particular function, and therefore to different Parkinson’s symptoms. In the future, cell transplants may include only specific subtypes for a more targeted therapy, he said.

Redmond’s lab is also trying to determine which growth factors will guide the organization of neuronal stem cells once they are transplanted. If developmental cues are absent when neurons are transplanted into adult brains, cells may not reach their designated target area. So far, Redmond and his team have tested glial cell line-derived neurotrophic factor (GDNF) as a possible instructional guide for stem cells in monkeys. The stem cells took root in the brains of 10 monkeys, they found, but after 11 months, only a small number of cells had differentiated into adult A9 dopaminergic neurons. To alleviate or cure Parkinson’s, enough transplanted stem cells must survive to replace the original dopamine cells that have died and organize themselves within the right place.

Earlier this year, Redmond harvested eggs from the ovaries of 30 monkeys to use in another promising technique in stem cell research: somatic cell nuclear transfer. Redmond and his team will place the nucleus of a skin cell into an egg cell whose nucleus has been removed. The modified egg cell will receive an electric shock to make it divide and reproduce. Ideally, this single cell will form a blastocyst, which contains stem cells. After changing into the right type of A9 neurons, these cells could be implanted into the brain of the monkey that provided the skin cells. Since the cells would be immunologically matched to the donor, enough cells might survive, and the result would be a long-term cure. “A few human patients treated with fetal dopamine cells have recovered and stayed better for periods of 10 or 15 years. I think it’s fair to say that there is proof of principle that this strategy will work,” Redmond said. “Now we have to create exactly the right cell to do the job reliably and permanently.”