Marius Wernig

Friday Stem Cell Roundup: Making Nerves from Blood; New Clues to Treating Parkinson’s

/ Todd Dubnicoff / 2 Comments

Stanford lab develops method to make nerve cells from blood.

wernig_ineurons_blood

Induced neuronal (iN) cells derived from adult human blood cells. Credit: Marius Wernig, Stanford University.

Back in 2010, Stanford Professor Marius Wernig and his team devised a method to directly convert skin cells into neurons, a nerve cell. This so-called transdifferentiation technique leapfrogs over the need to first reprogram the skin cells into induced pluripotent stem cells. This breakthrough provided a more efficient path to studying how genetics plays a role in various mental disorders, like autism or schizophrenia, using patient-derived cells. But these types of genetic analyses require data from many patients and obtaining patient skin samples hampered progress because it’s not only an invasive, somewhat painful procedure but it also takes time and money to prepare the tissue sample for the transdifferentiation method.

This week, the Wernig lab reported on a solution to this bottleneck in the journal, PNAS. The study, funded in part by CIRM, describes a variation on their transdifferentiation method which converts T cells from the immune system, instead of skin cells, into neurons. The huge advantage with T cells is that they can be isolated from readily available blood samples, both fresh or frozen. In a press release, Wernig explains this unexpected but very welcomed result:

“It’s kind of shocking how simple it is to convert T cells into functional neurons in just a few days. T cells are very specialized immune cells with a simple round shape, so the rapid transformation is somewhat mind-boggling. We now have a way to directly study the neuronal function of, in principle, hundreds of people with schizophrenia and autism. For decades we’ve had very few clues about the origins of these disorders or how to treat them. Now we can start to answer so many questions.”

Two studies targeting Parkinson’s offer new clues to treating the disease (Kevin McCormack)
Despite decades of study, Parkinson’s disease remains something of a mystery. We know many of the symptoms – trembling hands and legs, stiff muscles – are triggered by the loss of dopamine producing cells in the brain, but we are not sure what causes those cells to die. Despite that lack of certainty researchers in Germany may have found a way to treat the disease.

Mitochondria

Simple diagram of a mitochondria.

They took skin cells from people with Parkinson’s and turned them into the kinds of nerve cell destroyed by the disease. They found the cells had defective mitochondria, which help produce energy for the cells. Then they added a form of vitamin B3, called nicotinamide, which helped create new, healthy mitochondria.

In an article in Science & Technology Research News Dr. Michela Deleidi, the lead researcher on the team, said this could offer new pathways to treat Parkinson’s:

“This substance stimulates the faulty energy metabolism in the affected nerve cells and protects them from dying off. Our results suggest that the loss of mitochondria does indeed play a significant role in the genesis of Parkinson’s disease. Administering nicotinamide riboside may be a new starting-point for treatment.”

The study is published in the journal Cell Reports.

While movement disorders are a well-recognized feature of Parkinson’s another problem people with the condition suffer is sleep disturbances. Many people with Parkinson’s have trouble falling asleep or remaining asleep resulting in insomnia and daytime sleepiness. Now researchers in Belgium may have uncovered the cause.

Working with fruit flies that had been genetically modified to have Parkinson’s symptoms, the researchers discovered problems with neuropeptidergic neurons, the type of brain cell that helps regulate sleep patterns. Those cells seemed to lack a lipid, a fat-like substance, called phosphatidylserine.

In a news release Jorge Valadas, one of the lead researchers, said replacing the missing lipid produced promising results:

“When we model Parkinson’s disease in fruit flies, we find that they have fragmented sleep patterns and difficulties in knowing when to go to sleep or when to wake up. But when we feed them phosphatidylserine–the lipid that is depleted in the neuropeptidergic neurons–we see an improvement in a matter of days.”

Next, the team wants to see if the same lipids are low in people with Parkinson’s and if they are, look into phosphatidylserine – which is already approved in supplement form – as a means to help ease sleep problems.

CIRM-funded team uncovers novel function for protein linked to autism and schizophrenia

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Imagine you’ve just stopped your car at the top of the steepest street in San Francisco. Now, if want to stay at the top of the hill you’re going to need to keep your foot on the brakes. Let go and you’ll start rolling down. Fast.

Don’t step off the brake pedal! Photo: Wikipedia

Conceptually, similar decision points happen in human development. A brain cell, for instance, has the DNA instructions to become any cell in the body but must “keep the brakes on”, or repress, genes responsible for other cell types. Release the silencing of those genes and the brain cell’s properties will get pulled toward other fates.

That’s the subject of a CIRM-funded research study published today in Nature which reports on the identification of a new type of repressor protein which opens up a new understanding of how brain cells establish and keep their identity. That may not sound so exciting to our non-scientist readers but this discovery could lead to new therapy approaches for neurological disorders like autism, schizophrenia, major depression and low I.Q.

Skin cells to brain cells with just three genes
In previous experiments, this Stanford University research team led by Marius Wernig, showed it’s possible to convert a skin cell to a brain cell, or neuron, by adding just three genes to the cells, including one called Myt1l. The other two genes were known to act as master “on switches” that activate a cascade of genes responsible for making neuron-specific proteins. Myt1l also helped increase the efficiency of this direct reprogramming but it’s exact role in the process wasn’t clear.

Direct conversion of skin cell into a neuron.
Image: Wernig Lab, Stanford

A closer examination of Myt1l protein function revealed that instead of being an on switch for neuron-specific genes, it was actually an off switch for skin-specific genes. Now, there’s nothing unusual about the existence of a protein that represses gene activity to help determine cell identity. But up until now, these repressors were thought to be “lineage specific” meaning they specifically switched off genes of a specific cell type. For example, a well-studied repressor called REST affects cell fate by putting the brakes on only nerve-specific genes. The case of Myt1l was different.

Many but one
The researchers found that, in brain cells, Myt1l not only blocked the activation of skin-specific genes, it also shut down genes related to lung, cartilage, heart and other cells fates. The one set of genes that Mytl1 repressor did not appear to act on was neuron-specific genes. From these results a “many but one” pattern emerged. That is; it seems Myt1l helps drive and maintain a neuron cell fate by shutting off gene networks for many different cell identities except for neurons. It’s a novel way to regulate cell fate, as Wernig explained in a press release:

Marius Wernig
Photo: Steve Fisch

“The concept of an inverse master regulator, one that represses many different developmental programs rather than activating a single program, is a unique way to control neuronal cell identity, and a completely new paradigm as to how cells maintain their cell fate throughout an organism’s lifetime.”

To build a stronger case for Myt1l function, the team looked at the effect of blocking the protein in the developing mouse brain. Sure enough, lifting Myt1l repression lead to a decrease in the number of neurons in the brain. Wernig described the impact of also inhibiting Myt1l in mature neurons:

“When this protein is missing, neural cells get a little confused. They become less efficient at transmitting nerve signals and begin to express genes associated with other cell fates.”

Potential cures can be uncovered withfundamental lab research
It turns out that Myt1l mutations have been recently found in people with autism, schizophrenia, major depression and low I.Q. Based on their new insights, the author suggest that in adults, these disorders may be caused by a neuron’s inability to maintain its identity rather than by a more permanent abnormality that occurred during fetal brain development. This hypothesis presents the exciting possibility of developing therapies that could improve symptoms.

Using stem cells paves new approach to treating a blistering skin disease

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Imagine a child not being able to run or jump or just roll around, for fear that any movement could strip away their skin and leave them with open, painful wounds. That’s what life is like for children with a nasty genetic disease called epidermolysis bullosa or EB. The slightest touch can cause their skin to peel off. People with the disease often die in their late teens or early 20’s from skin cancer, caused by repeated cycles of skin wounding and healing.

Now Stanford researchers, funded by the stem cell agency, have found a way to correct the faulty gene and grow healthy skin, a technique that could completely change the lives of children with EB. This new approach, which the researchers call “therapeutic reprogramming”, is reported in the journal Science Translational Medicine

In the study the researchers took skin cells from patients with EB and reprogrammed them to become induced pluripotent stem (iPS) cells that have the ability to become any of the other cells in the body. They then replaced the faulty gene that caused that particular form of EB and then turned the cells into keratinocytes, the cells that make up most of our outer layer of skin. When they grafted these cells onto the back of laboratory mice they grew into normal human skin.

In a news release about the work, Dr. Anthony Oro, one of the senior authors of the paper, says the work represents a completely different approach to treating EB.

“Normally, treatment has been confined to surgical approaches to repair damaged skin, or medical approaches to prevent and repair damage. But by replacing the faulty gene with a correct version in stem cells, and then converting those corrected stem cells to keratinocytes, we have the possibility of achieving a permanent fix — replacing damaged areas with healthy, perfectly matched skin grafts.”

One of the key words in that quote is “healthy”. Because the skin cells that they got from the patient probably already included some that had a skin cancer-causing mutation, the researchers carefully screened the cells to make sure they removed any that looked suspicious.

Oro says tests showed the resulting skin from these iPS cells was very similar to human skin made from normal keratinocytes.

“The most difficult part of this procedure is to show not just that you can make keratinocytes from the corrected stem cells, but that you can then use them to make graftable skin. What we’d love to do is to be able to give patients healthy skin grafts on the areas that they bang a lot, such as hands and feet and elbows — those places that don’t heal well. That alone would significantly improve our patients’ lives. We don’t know how long these grafts might last in humans; we may need some improvements. But I think we’re getting very close.”

Having seen that this works in mice the team are now eager to see if they can replicate their results in people. With CIRM support they have already been working with the Food and Drug Administration (FDA) to pave the way for that to happen. Dr. Marius Wernig, one of the senior authors of the paper, says that focus on patients is driving their work:

“CIRM made sure that we were always keeping in mind the need to translate our results to the clinic. Now we’ve shown that this approach that we call ‘therapeutic reprogramming’ works well with human cells. We can indeed take skin cells from people with epidermolysis bullosa, convert them to iPS cells, replace the faulty collagen 7 gene with a new copy, and then finally convert these cells to keratinocytes to generate human skin. It is almost like a fountain of youth that, in principle, produces an endless supply of new, healthy skin from a patient’s own cells.”