18 March 2013

Fibroblast neurons are the hope for the development of personalized regenerative medicine

Autologous neural progenitor cells successfully transplanted into monkey brains

LifeSciencesToday based on UW-Madison: Transplanted brain cells in monkeys light up personalized therapyFor the first time, scientists transplanted neural progenitor cells derived from monkey skin cells into the brains of the same animals and observed their differentiation into several types of mature neural cells.

The cells looked perfectly normal for six months, and they could only be detected because they were labeled with a fluorescent protein.

Since the cells were obtained from differentiated skin cells of precisely those monkeys into whose brains they were subsequently transplanted, this experiment is proof of the validity of the concept of personalized medicine, in which treatment is developed individually for each patient.

Since the skin cells were not "foreign" tissue, the scientists did not observe any signs of their immune rejection – one of the main problems that arise when working with cell transplants.

"Looking at such a brain, you can't say that it's a transplant," says study leader Su-Chun Zhang, MD, PhD, professor of neurology at the University of Wisconsin-Madison. "Structurally, the brain of the host organism looks like a normal brain; the graft can only be seen under a fluorescent microscope."

"This is the first time I have observed such a good integration of transplanted cells in monkeys, with such a minimal reaction. And after six months, there was not even a noticeable scar," says Marina Emborg, MD, PhD, associate professor of the Department of Medical Physics at UW–Madison, the lead co-author of the study.

Induced pluripotent stem cells (iPSCs) offer broad prospects for the development of personalized cell therapy. Scientists have shown that autologous neural progenitors obtained from iPSCs survive for 6 months and differentiate into neurons, astrocytes and myelinating oligodendrocytes in the brains of rhesus monkeys with artificially induced Parkinson's disease with minimal inflammatory response. This discovery represents a big step towards personalized regenerative therapy. (Fig. cell.com/cell-reports )

The cells were implanted into the brains of monkeys with artificially induced symptoms of Parkinson's disease using a state-of-the-art surgical procedure accompanied by MRI imaging. The cause of the development of Parkinson's disease is the death of a small number of neurons that produce the signaling chemical dopamine. About 1 million people suffer from this disease in the USA alone.

The transplanted cells were derived from induced pluripotent stem cells, which, like embryonic stem cells, can develop into almost any cell in the body.

Induced pluripotent stem cells were reprogrammed into neural progenitor cells. Progenitor cells that are at an intermediate stage of differentiation further specialize into neurons that transmit nerve impulses, or glial cells that perform many functions necessary for brain tissue. This final stage of differentiation took place already in the brain of monkeys.

Professor Zhang, who was the first in the world to receive neural cells from embryonic and then from induced pluripotent stem cells, believes that one of the keys to success was precise control over the differentiation process.

"We differentiated stem cells only into neural cells. If the transplanted cell population had been contaminated with non-nerve cells, nothing would have happened," the scientist says. "Obtaining animal cells and returning them in a new form to the same animal is the first step towards personalized medicine. ...Now our goal is to move forward and see if this will become a real method of treating this terrible disease."

Another encouraging sign is the absence of any signs of cancer development - an alarming potential result of stem cell transplantation.

"They look normal, and besides, we used antibodies that mark rapidly dividing cells, such as cancer cells, and we don't see them binding. These cells became neurons with long axons, as we expected. Oligodendrocytes have also developed from them, helping to build insulating myelin sheaths of neurons, as it should be. This means that they have matured correctly and are not malignant."

The experiment was conceived as a proof of principle, continues Professor Zhang, who heads a group developing pioneering methods for using induced pluripotent stem cells at the UW-Madison Weisman Center. A small number of cells were transplanted into the animals' brains – insufficient to replenish the natural population of dopamine-producing neurons – and the clinical picture of the disease in macaques has not changed.

A neuron created in the laboratory of Professor Su-Chun Zhang at the University of Wisconsin-Madison produces the neurotransmitter dopamine. It is derived from induced pluripotent stem cells, the source of which were mature skin cells of rhesus monkeys. Professor Zhang's research is proof that personalized medicine will one day be able to cure Parkinson's disease. (Yan Liu and Su-Chun Zhang, Waisman Center, University of Wisconsin-Madison)Despite the promise of the cell transplantation method, its clinical application is still very far away, adds Professor Zhang.

"Unfortunately, this method cannot be used to help patients until answers are received to a number of questions: can such a transplant alleviate the symptoms of the disease? How safe is it? Six months is not enough time… What are the side effects? It's possible to mitigate some of the symptoms, but if it leads to something else, then we haven't solved the problem."

"This is really the first transplantation of induced pluripotent stem cells of monkeys to the same animal, and not only to the brain," sums up Professor Zhang. "I have not heard of anyone transplanting reprogrammed iPSCs into the blood, pancreas or anywhere else to the same monkey. This study gives hope for the development of personalized regenerative medicine."

Article by Emborg et al. Induced Pluripotent Stem Cell-Derived Neural Cells Survive and Mature in the Nonhuman Primate Brain is published in the journal Cell Reports.

Portal "Eternal youth" http://vechnayamolodost.ru18.03.2013

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