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.

Brain Regeneration: Mouse Brains and Human Futures

Embryonic stem cells are surprisingly capable of regenerating portions of the brains of mice according to a report published in the November 25 issue of the journal Science. What is unexpected about this report is not the extent of the repairs so much as where they occurred in the brain.

The hypothalamus, which is involved basic metabolism and complex behaviors, has usually been regarded as less open to regeneration, whether naturally or by biomedical intervention. Naturally, a limited number of neurons develop during adulthood, but these are not enough to restore this area of the brain after injury or disease. “The neurons that are added during adulthood in both regions are generally smallish and are thought to act a bit like volume controls over specific signaling,” explained Jeffrey Macklis of Harvard Medical School and one of the lead researchers in the study.

“Here we've rewired a high-level system of brain circuitry that does not naturally experience neurogenesis,” Macklis said, “and this restored substantially normal function.”

The report reached this conclusion: “these experiments demonstrate that synaptic integration… [by] donor neurons can impart an organism-level rescue of metabolic defects, thereby providing a proof of concept for cell-mediated repair of a neuronal circuit controlling a complex phenotype.”

While it is important to underscore that this work is performed on mice, the results suggest that something similar might be possible someday in human beings with brain injuries. “The finding that these embryonic cells are so efficient at integrating with the native neuronal circuitry makes us quite excited about the possibility of applying similar techniques to other neurological and psychiatric diseases of particular interest to our laboratory," according to Matthew Anderson in a press release issued by Harvard Medical School.

For now, research continues using mice as models for human disease or spinal cord injury. “The next step for us is to ask parallel questions of other parts of the brain and spinal cord, those involved in ALS and with spinal cord injuries,” according to Macklis. "In these cases, can we rebuild circuitry in the mammalian brain? I suspect that we can."

This study, coming so quickly on the heels of another report showing the functional integration of human embryonic stem cells into the mouse brain, suggests that embryonic stem cell research may indeed open new ways to treat brain disease or injury. Both studies, however, open the possibility that the use of technologies of brain regeneration will not stop with disease. As always, the growing power of medicine to treat disease is also an expansion of the possibility of human enhancement. All this if far in the future. But already, advocates of human enhancement have noticed its significance. See, for example, the re-posting of the original press release on Ray Kurweil's transhumanist blog.

The report, entitled “Transplanted Hypothalamic Neurons Restore Leptin Signaling and Ameliorate Obesity in db/db Mice,” appears in the November 25, 2011 issue of Science.