Stem Cell Advance: Brain Cells Inserted in Monkey Brains

Researchers at the University of Wisconsin-Madison are reporting a significant step forward toward the day when stem cells may be used to treat brain diseases such as Parkinson’s.

Working with three rhesus monkeys, the research team created a personalized stem cell culture for each monkey.  Cells taken from the skin of the monkey were induced to a state of pluripotency by means of a process called “induced pluripotency.”  Once in a state of pluripotency, the cells were guided forward in the process of differentiation until they became neurons and glial cells.  Along the way, the cells in the culture were given a genetic tag so the cells would glow under a florescent light. 

Then the cells were implanted in the brains of the rhesus monkeys.  Because the source of the cells was the monkeys themselves, the DNA matched and there was no immune reaction.  After six months, researchers discovered that the cells were so fully integrated into the monkey brains that in many cases, they could only be recognized by their green florescent glow.

"When you look at the brain, you cannot tell that it is a graft," says senior author Su-Chun Zhang, according to a press release from the University of Wisconsin. "Structurally the host brain looks like a normal brain; the graft can only be seen under the fluorescent microscope." 

Caption: 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.  Image: courtesy Yan Liu and Su-Chun Zhang, Waisman Center, University of Wisconsin–Madison.

The three monkeys involved in the experiment were given tiny lesions or scars in their brain to mimic Parkinson’s disease.  Another lead researcher, Marina Emborg, commented on how the inserted cells integrated themselves into the brain.  “After six months, to see no scar, that was the best part."

What makes this work significant is that it is the first use of induced pluripotent stem cells (iPS) involving a primate, setting the stage for further work someday involving human beings.  According to Zhang, "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."

One of the keys to their success is that the iPS cells themselves were not transplanted into the monkeys.  Because iPS cells are pluripotent, they can give rise to cancer or other problems.  In this work, the researchers carefully guided the iPS cells so that they were almost at the final stage of differentiation, and then made sure that their cell culture was completely purified so that no potentially cancer-causing cells would slip through.  Quoting Zhang once again: "We differentiate the stem cells only into neural cells. It would not work to transplant a cell population contaminated by non-neural cells."

Because of these precautions, the experiment succeeded in introducing new cells into the monkey’s brains without any obvious problems.  But in this experiment, too few cells were introduced to help the monkeys overcome the symptoms of Parkinson’s.  Solving that problem is the obvious next step.

According to the paper, “this finding represents a significant step toward personalized medicine,” which may someday be used to treat a wide range of diseases in humans.  Because the original source of the cells was from the individual monkeys themselves, there was no immune rejection.  If the same technique can be applied to human beings, it may mean that an individualized culture of iPS cells could be created for each patient, then carefully guided forward in the process of differentiation, and then implanted to regenerate organs or tissues damaged by injury or disease.

What makes iPS cells especially attractive is that no embryos are used in their creation, and so almost no one objects to this line of medical research.  But if regenerative medicine is successful, someday it will be used not just to treat disease but to off-set the effects of aging or to enhance those who are well.  Then, we can be sure, many will object to this technology, but even more will use it.

The article, entitled “Induced Pluripotent Stem Cell-DerivedNeural Cells Survive and Mature in the Nonhuman Primate Brain,” is freely available at the open access journal, Cell Reports in its March 28, 2013 issue. 

 

A New Source for New Neurons

The day when stem cell research will give us treatments for common brain disorders such as Parkinson’s or Alzheimer’s just got a little closer. So, by the way, did the day when this research will be used to enhance the capacities of the normal or healthy human brain. The latest advance comes from an international team based mostly in Germany, which has figured out a way to generate new neurons from cells that already exist in the human brain.

The human brain naturally contains specialized cells called pericytes. Usually they are located at the edge of the capillaries that carry blood to the brain. They play a vital role in maintaining the blood-brain barrier.

Neurons. Photo from National Institutes of Health.

Now, thanks to the discovery reported in the October 5 issue of Cell Stem Cell, pericytes might be about to learn a new trick: forming new neurons. Using stem cell reprogramming techniques, researchers learned that two factors—Sox2 and Mash1—would induce pericytes to change their developmental state and begin to function as newly-formed neurons.

According to the article, “these induced neuronal cells acquire the ability of repetitive action potential firing and serve as synaptic targets for other neurons, indicating their capability of integrating into neuronal networks.” In other words, they do what neurons normally do. They process signals from one end of the cell to another. They form synaptic connections with other neurons. And they integrate into larger networks.

Will this become a new strategy for treating diseases or injuries to brain cells? That is the hope, but difficult challenges remain. How can living pericytes in a functioning human brain be targeted and induced to become neurons? If they generate new neurons, will they function properly? Will they integrate themselves into a functioning brain, preferably taking up the cognitive processes that are lost because of disease or injury?

The authors conclude that “much needs to be learned” but that “our data provide strong support for the notion that neuronal reprogramming of cells of pericytic origin within the damaged brain may become a viable approach to replace degenerated neurons.”

According to Benedikt Berninger of the Johannes Gutenberg University in Mainz, a leader in the research team, “The ultimate goal we have in mind is that this may one day enable us to induce such conversion within the brain itself and thus provide a novel strategy for repairing the injured or diseased brain."

That may be the goal, but it's hard to imagine this research will be limited to therapy. In fact it may turn out to be easier to use it to enhance the cognitive capacity of normal or healthy aging brains than it is to treat disease. Anything that stimulates the growth of new neurons is likely to be very appealing to aging adults.

If human stem cell research is to reach its full promise, many more advances like this will have to occur. With each advance, however, comes growing confidence that the promise of the field may be highly challenging, but it is not hype.

The article entitled “Reprogramming of pericyte-derived cells of the adult human brain into induced neuronal cells” is published in the October 4, 2012 issue of Cell Stem Cell.