Adult, Embryonic, and Induced Pluripotent Stem Cells – Who’s ready for prime time?

The CosmeticSurg Blog has an excellent summary of the number of clinical trials using adults vs. embryonic and induce pluripotent stem cells by Ricardo L Rodriguez, MD. Folks, the number isn’t even close.

The graphics in this article are a hoot and make the point splendidly. Check out the article here.

How Brain Stem Cells Stay Asleep or Get With It

Our brains are filled with stem cells that help in learning and memory and also respond to stress and various types of drugs. How do we regulate these stem cells so that we do not overuse them and then eventually use them up?

Johns Hopkins University researchers have discovered how brain stem cells switch between a dormant state and an active state that creates new brain cells. These stem cells detect chemical communication signals passes between nearby neurons, and these signals cause the stem cells to toggle between the active and dormant state, depending on the stress on the brain and its needs at the time.

Hongjun Song, professor of neurology and director of Johns Hopkins Medicine’s Institute for Cell Engineering’s Stem Cell Program, put it this way: “What we have learned is that brain stem cells don’t communicate in the official way that neurons do, through synapses or by directly signaling each other.” He continued: “Synapses, like cell phones, allow nerve cells to talk to each other. Stem cells don’t have synapses, but out experiments show they indirectly hear the neurons talking to each other; it’s like listening to someone near you talking on a phone.”

There is great importance for this finding for psychiatry, since the brain reacts to its environment and stress and steroids can decrease the number of brain cells, where as some antidepressants can increase the number of brain cells.

What then is this “indirect talk” that these brain stem cells are able to access? It is apparently composed of chemical messages that result from the neurotransmitters released by neurons. Neurons are the cells in the nervous system that are capable of propagating nerve impulses. When the nerve impulse reaches the end of the neuron, the end of the neuron, also known as the axon terminus, releases a chemical called a neurotransmitter. The neurotransmitter bathes the adjoining neuron and, depending on the particular neurotransmitter released by the upstream neuron, either stimulates it to propagate and nerve impulse, or prevents it from initiating a nerve impulse. Neurons, therefore, talk to one another by means of neurotransmitter release, and the connections between neurons are specialized structures called “synapses.”

Neurons release lots of neurotransmitter, but there are several mechanisms that regulate how much neurotransmitter the downstream neuron is exposed to. Enzymes on the surface of the neuron degrade unbound neurotransmitters and uptake receptors suck up unused neurotransmitter. One of these enzymes that degrade particular types of neurotransmitters, monoamine oxidase, is a target of particular antidepressants (monoamine oxidase inhibitors or MAOIs, such as Minaprine also known as Cantor, Pirlindole AKA Pirazidol, Toloxatone AKA Humoryl, Pargyline AKA Eutonyl, or Rasagiline AKA Azilect), since they increase the concentration of particular neurotransmitters and increase their effectiveness.

Which neurotransmitter can brain stem cells detect? In their experiments, the Johns Hopkins University research group used laboratory mice. They isolated the brain stem cells, and then used a technically demanding technique called “patch clamping to detect changes in electric charge across the cell surfaces after the addition of particular neurotransmitters. The neurotransmitter that seemed to work the best was GABA (gamma-amino-butyric acid), which is a well-known inhibitor neurotransmitter.

To ensure that they were not barking up the wrong tree, Song and his group used genetic engineering techniques to remove the gene that encodes the GABA receptor from the stem cells. The stem cells that were unable to detect GABA replicated and produced glial cells (those cells that support neurons). However, those stem cells that still had their GABA receptors stayed dormant and did not make new cells.

In their next experiment, Song’s group treated mice with a drug called valium, which is an anti-anxiety drug that acts like GABA, since it activates the GABA receptor. They waited two to seven days and examined the brain stem cells in mice treated with GABA and mice not treated with GABA. The treated mice had many more dormant stem cells than those that were not treated with valium.

According to Song, “Traditionally GABA tells neurons to shut down and not continue to propagate a message to other neurons. In this case the neurotransmitter also shuts off the stem cells and keeps them dormant.”

The brain stem cells have access to GABA because they are typically surrounded by as many as 10 different kinds of intermingled neurons.   Even though any of these neurons could potentially signal to the stem cells and keep them in their dormant state, Song’s work clearly shows that it is the GABA-releasing neurons that are controlling them.  The stem cells are able to sense GABA because a specific group of “interneurons” that are attached to neurons and to the stem cells bring the GABA to them.  Song and his group determined this by using a technique called “optogenetics,” in which they inserted special light-activating proteins into the neurons that trigger the cells to send a neural impulse and release their neurotransmitter once a light is shined on them. This experiment established that a group of interneurons known as the parvalbumin-expressing interneurons signal to the stem cells from the GABA-releasing neurons.

Their final experiment, they socially isolated normal mice and mice whose brain-specific stem cells lack the GABA receptor. After one week of social isolation, normal mice had an increase in neurons and glial cells that were the result of dividing stem cells. The mutant mice, however, showed no such increases.

Song concluded, “GABA communication clearly conveys information about what brain cells experience of the outside world, and, in this case, keeps the brain stem cells in reserve, so if we don’t need them, we don’t use them up.”

This research was published in Nature, 2012; DOI:10.1038/nature11306.