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Stem Cells Make Neurons, and Tumors, in Rat Model of Parkinson's Disease

For release: Thursday, March 1, 2007

In a new study that illustrates the promise and perils of stem cell therapy, scientists found that implanting human embryonic stem cells led to dramatic functional improvement – but also to brain tumors – in a rat model of Parkinson’s disease (PD).

Since their isolation in the 1980s, human embryonic stem cells – which are capable of generating nearly all the cells that make up the human body – have been eyed as a potential toolkit for treating PD and a host of other diseases.  The challenge is getting them to turn into the needed cell type.  Without the proper cues, they could simply make more of themselves, possibly leading to tumors.

PD is characterized by gradually worsening tremor, slowness of movement, and stiffened muscles.  It’s considered an ideal candidate disease for stem cell therapy because it damages a relatively small population of neurons.  Those neurons produce the chemical dopamine, and make their home in a brain region known as the substantia nigra, which connects to another region called the striatum.

The new study, published in Nature Medicine,*describes a high-yield method for inducing human embryonic stem cells to become dopaminergic neurons.  When those neurons were implanted into the striatum of rats with a condition similar to PD, the rats ultimately recovered their full motor functions.  Disturbingly, however, a small fraction of the implanted cells formed tumors.

“The cells were on their way to becoming neurons, but kept dividing after we transplanted them,” explained Steven Goldman, M.D., Ph.D., the study’s senior author and a neurologist at the University of Rochester Medical Center in New York.  He is hopeful that the rogue cells can be culled away prior to transplantation.

Previous studies have shown that stem cell transplants are beneficial in animal models of PD, Dr. Goldman said.  However, this study, which was supported by the National Institute of Neurological Disorders and Stroke (NINDS), is the first to show that human-derived cells are capable of producing therapeutic effects on a par with those of animal-derived cells.  Human stem cells are more likely to work in patients, because they are less likely to trigger immune rejection than animal cells.

To devise a way of coaxing embryonic stem cells to become striatal neurons, Dr. Goldman collaborated with Neeta Roy, Ph.D., a former researcher in his lab, now a professor of neuroscience at Weill Medical College of Cornell University in New York.  Drs. Goldman and Roy figured they could send the cells down the right path if they grew them under laboratory conditions that mimicked the natural environment of young striatal neurons.  So, they grew the stem cells in the presence of astrocytes – cells that nourish and guide developing neurons – isolated from a part of the developing brain that eventually gives rise to the substantia nigra.

The researchers then tested the stem cells in rats that had been given a toxin to destroy their dopaminergic neurons, transplanting them after the rats began to show motor control problems.  Over a few months, the treated rats showed consistent improvement on behavioral tests, ultimately performing as well as normal rats that had never received the toxin.

Anatomical studies revealed that the transplanted cells had homed to damaged areas, and morphed – or “differentiated” into – dopaminergic neurons.  Within each transplant, however, some cells continued to reproduce themselves rather than differentiate.

The dividing cells, Dr. Goldman said, were not invasive cancers, meaning that they didn’t spread beyond the transplant site to distant regions of the brain or to other tissues.  That scenario has been a longstanding concern among stem cell researchers.

“It’s fair to call them tumors, though,” said Dr. Goldman.

“The silver lining,” he said, “is that we should be able to purify the neurons and separate them from the undifferentiated cells that remain in the mix.”  He and his colleagues are currently developing a procedure that would allow them to distinguish neurons from non-neurons using fluorescently-tagged proteins.

*Roy NS et al.  “Functional Engraftment of Human ES Cell-Derived Dopaminergic Neurons Enriched by Coculture with Telomerase-Immortalized Midbrain Astrocytes.”  Nature Medicine, November 2006, Vol. 12(11), pp. 1259-1268.

-By Daniel Stimson, Ph.D.

Last Modified March 1, 2007