Thursday, 14 March 2013

Transplanted Brain Cells in Monkeys Light Up Personalized Therapy

UW study is key step toward treating disease with stem cells
Thursday, 14 March 2013

For the first time, scientists have transplanted neural cells derived from a monkey's skin into its brain and watched the cells develop into several types of mature brain cells, according to the authors of a new study in Cell Reports. After six months, the cells looked entirely normal, and were only detectable because they initially were tagged with a fluorescent protein.

Because the cells were derived from adult cells in each monkey's skin, the experiment is a proof-of-principle for the concept of personalized medicine, where treatments are designed for each individual.

And since the skin cells were not "foreign" tissue, there were no signs of immune rejection — potentially a major problem with cell transplants.

Standing at centre, Su-Chun Zhang, professor of 
neuroscience in the School of Medicine and Public 
Health, talks with his staff as they prepare stem-cell 
cultures in the Zhang's research lab at the Waisman 
Center at the University of Wisconsin–Madison on 
March 8, 2013. Pictured at right are postdoctoral 
students Yan Liu, background, and Lin Yao, 
foreground. Credit: Photo by Jeff Miller.
"When you look at the brain, you cannot tell that it is a graft," says senior author Su-Chun Zhang, a professor of neuroscience at the University of Wisconsin-Madison.

"Structurally the host brain looks like a normal brain; the graft can only be seen under the fluorescent microscope."

“This is the first time I saw, in a nonhuman primate, that the transplanted cells were so well integrated, with such a minimal reaction. And after six months, to see no scar, that was the best part," Marina Emborg says, an associate professor of medical physics at UW-Madison and the lead co-author of the study. "

The cells were implanted in the monkeys "using a state-of-the-art surgical procedure" guided by an MRI image, says Emborg. The three rhesus monkeys used in the study at the Wisconsin National Primate Research Center had a lesion in a brain region that causes the movement disorder Parkinson's disease, which afflicts up to 1 million Americans. Parkinson's is caused by the death of a small number of neurons that make dopamine, a signalling chemical used in the brain.

The transplanted cells came from induced pluripotent stem cells (iPS cells), which can, like embryonic stem cells, develop into virtually any cell in the body. iPS cells, however, derive from adult cells rather than embryos.

In the lab, the iPS cells were converted into neural progenitor cells. These intermediate-stage cells can further specialize into the neurons that carry nerve signals, and the glial cells that perform many support and nutritional functions. This final stage of maturation occurred inside the monkey.

Zhang, who was the first in the world to derive neural cells from embryonic stem cells and then iPS cells, says one key to success was precise control over the development process.

"We differentiate the stem cells only into neural cells. It would not work to transplant a cell population contaminated by non-neural cells."

Another positive sign was the absence of any signs of cancer, says Zhang — a worrisome potential outcome of stem cell transplants.

This neuron, created in the Su-Chun Zhang lab at the 
University of Wisconsin–Madison, makes dopamine, 

a neurotransmitter involved in normal movement. The 

cell originated in an induced pluripotent stem cell, which 
derive from adult tissues. Similar neurons survived and 
integrated normally after transplant into monkey brains 
— as a proof of principle that personalized medicine may 
one day treat Parkinson's disease (Date: 2010). Credit
courtesy by Yan Liu and Su-Chun Zhang, Waisman 
Center, University of Wisconsin–Madison. 
"Their appearance is normal, and we also used antibodies that mark cells that are dividing rapidly, as cancer cells are, and we do not see that. And when you look at what the cells have become, they become neurons with long axons [conducting fibres], as we'd expect. They also produce oligodendrocytes that are helping build insulating myelin sheaths for neurons, as they should. That means they have matured correctly, and are not cancerous."

The experiment was designed as a proof of principle, says Zhang, who leads a group pioneering the use of iPS cells at the Waisman Center on the UW-Madison campus. The researchers did not transplant enough neurons to replace the dopamine-making cells in the brain, and the animal's behaviour did not improve.

Although promising, the transplant technique is a long way from the clinic, Zhang adds.

"Unfortunately, this technique cannot be used to help patients until a number of questions are answered: Can this transplant improve the symptoms? Is it safe? Six months is not long enough. And what are the side effects? You may improve some symptoms, but if that leads to something else, then you have not solved the problem."

Nonetheless, the new study represents a real step forward that may benefit human patients suffering from several diseases, says Emborg.

"By taking cells from the animal and returning them in a new form to the same animal, this is a first step toward personalized medicine."

The need for treatment is incessant, says Emborg, noting that each year, Parkinson's is diagnosed in 60,000 patients.

"I'm gratified that the Parkinson's Disease Foundation took a risk as the primary funder for this small study. Now we want to move ahead and see if this leads to a real treatment for this awful disease."

"It's really the first-ever transplant of iPS cells from a non-human primate back into the same animal, not just in the brain," says Zhang.

"I have not seen anybody transplanting reprogrammed iPS cells into the blood, the pancreas or anywhere else, into the same primate. This proof-of-principle study in primates presents hopes for personalized regenerative medicine."

Contact: Su-Chun Zhang

Reference:
Induced Pluripotent Stem Cell-Derived Neural Cells Survive and Mature in the Nonhuman Primate Brain
Marina E. Emborg, Yan Liu, Jiajie Xi, Xiaoqing Zhang, Yingnan Yin, Jianfeng Lu, Valerie Joers, Christine Swanson, James E. Holden, Su-Chun Zhang
Cell Reports, 14 March 2013, 10.1016/j.celrep.2013.02.016
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