Stem cell stories that caught our eye: Amy Schumer’s MS fundraising; healing traumatic brain injury; schizophrenia iPS insights

Amy Schumer and Paul Shaffer raise money for MS. (Karen Ring)
Two famous individuals, one a comedian/movie star, the other a well-known musician, have combined forces to raise money for an important cause. Amy Schumer and Paul Shaffer have pledged to raise $2.5 million dollars to help support research into multiple sclerosis (MS). This disease affects the nerve cells in both the brain and spinal cord. It eats away at the protective myelin sheaths that coat and protect nerve cells and allow them to relay signals between the brain and the rest of the body. As a result, patients experience a wide range of symptoms including physical, mental and psychiatric problems.

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Comedian Amy Schumer and her Dad who has MS.
(National MS Society)

The jury is still out on the exact cause of MS and there is no cure available. But the Tisch MS Research Center of New York is trying to change that. It is “dedicated to finding the cause and cure for MS” and recently announced, at its annual Future Without MS Gala, that it has pledged to raise $10 million to fund the stem cell research efforts ongoing at the Center. Currently, Tisch is “the only center with an FDA approved stem cell clinical trial for MS in the United States.” You can read more about this clinical trial, which is transplanting mesenchymal stem cell-derived brain progenitor cells into the spinal cord, on the Tisch website.

At the gala, both Amy Schumer and Paul Shaffer were present to show their support for MS research. In an interview with People magazine, Amy revealed that her father struggles with MS. She explained, “Some days he’s really good and he’s with it and we’re joking around. And some days I go to visit my dad and it’s so painful. I can’t believe it.” Her experience watching her dad battle with MS inspired her to write and star in the movie TRAINWRECK, and also to get involved in supporting MS research. “If I can help at all I’m gonna try, even if that means I’ll get hurt,” she said.

Stem cells may help traumatic brain injuries (Kevin McCormack
Traumatic brain injury (TBI) is a huge problem in the US. According to the Centers for Disease Control and Prevention around 1.7 million Americans suffer a TBI every year; 250,000 of those are serious enough to result in a hospitalization; 52,000 are fatal. Even those who survive a TBI are often left with permanent disabilities, caused by swelling in the brain that destroys brain cells.

Now researchers at the University of Texas Health Science Center at Houston say using a person’s own stem cells could help reduce the severity of a TBI.

The study, published in the journal Stem Cells, found that taking stem cells from a person’s own bone marrow and then re-infusing them into the bloodstream, within 48 hours of the injury, can help reduce the swelling and inflammation that damages the brain.

In an interview with the Houston Chronicle Charles Cox, the lead researcher – and a member of CIRM’s Grants Working Group panel of experts – says the results are not a cure but they are encouraging:

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Charles Cox
(Drew Donovan / UTHealth)

“I’m talking about the difference between someone who recovers to the point that they can take care of themselves, and someone who is totally dependent on someone else for even simple tasks, like using the bathroom and bathing. That’s a dramatic difference.”

Schizophrenia: an imbalance of brain cell types?

Schizophrenia is a chronic mental disorder with a wide range of disabling symptoms such as delusional thoughts, hearing voices, anxiety and an inability to experience pleasure. It’s estimated that half of those with schizophrenia abuse drugs and alcohol, which likely contributes to increased incidence of unemployment, homelessness and suicide. No cure exists for the disorder because scientists don’t fully understand what causes it, and available treatments only mask the symptoms.

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A patient’s artistic representation of living with schizophrenia
(Wikipedia)

This week, researchers at the RIKEN Brain Science Institute in Japan reported new clues about what goes wrong at a cellular and molecular level in the brains of people with schizophrenia. The scientists created induced pluripotent stem cells (iPSCs) from healthy donors, as well as patients with schizophrenia, and then changed or specialized them into nerve cells, or neurons. They found that fewer iPSCs developed into neurons when comparing the cells from people with schizophrenia to the healthy donor cells. Instead, more iPSCs specialized into astrocytes, another type of brain cell. This fewer neurons/more astrocytes shift was also seen in brains of deceased donors who had schizophrenia.

Looking inside the cells, the researchers found higher levels of a protein called p38 in the neurons derived from the people with schizophrenia. Inhibiting the activity of p38 led to increased number of neurons and fewer astrocytes, which resembles the healthy state. These results, published in Translational Psychiatry and picked up by Health Canal, point to inhibitors of p38 activity as a potential path for developing new treatments.

Stem cells provide promising skin in the game for treating burn victims

For severe burn victims and others in need of skin transplants, current treatments using artificial skin grafts made from sheets of lab-grown skin cells aren’t ideal because they lack the complex structures needed to fully restore many of the skin’s critical functions.

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The skin isn’t just a layer of covering for our body. It’s a complex organ with many structures that work together to protect us from infection, regulate our body temperature and allow us to sense the outside world.
Image credit: Wikimedia Commons

For example, artificial skin doesn’t contain oil-producing sebaceous glands and forces burn victims to relentlessly apply oil to their skin grafts in order to prevent them from drying out and losing their natural cushioning and waterproof properties.  Without the replacement of sweat glands and hair follicles within the skin tissue, the graft regions don’t adequately regulate body temperature. And the sense of touch is often lost as disrupted nerve fibers aren’t reconnected to transplanted skin.

The lack of a genuine skin replacement has emotional consequences too since skin grafts often don’t match up with surrounding skin and leaves victims disfigured. So, while current treatments help, the field is busily looking for new and better solutions.

New skin in the game
As reported in the latest issue of Science Advances, a research team from the RIKEN Center for Developmental Biology in Japan has taken a major step in the right direction by generating a fully functional 3D skin organ system in mice using stem cells.

The team accomplished this feat by first collecting gum cells from the mouth of the mouse and reprogramming them into induced pluripotent stem cells (iPS) which can specialize into any cell type of the body. After a few days in a petri dish, the iPS cells formed into embryoid bodies, clumps of cells that contain a random mix of cell types that would be seen in a developing embryo, including those that give rise to skin. Then, using a novel transplantation method, a cluster of several embryoid bodies were encased together in a gel and then transplanted into mice where they could grow for later testing.

Skin that sweats and grows hair

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Image credit: Tsuji et al./RIKEN

The embryoid body clusters were allowed to further develop in the mice for a month. The transplants were then taken out and their cellular structure and gene activity were analyzed. The results confirmed the formation of a complex, three-dimensional skin organ system complete with all three skin layers as well as hair follicles, sweat glands, oil-producing sebaceous glands and fat tissue.

In follow up experiments, small pieces of this tissue were transplanted into the skin of another set of mice. After 14 days, the researchers observed new hair growth from the follicles of the transplanted tissue. They also showed that the hair follicles had made the necessary connections to muscle tissue and nerve fibers of the host mice.

Future directions
Translating this method for humans is years away but this data provides an important step toward a new generation of regenerative skin grafts that are fully functional as a complex organ system and not as just a two dimensional sheet of skin cells.

As study leader Takashi Tsuji mentions in a press release, skin transplants are not the only potential application of their technique:

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Takashi Tsuji

“With this new technique, we have successfully grown skin that replicates the function of normal tissue. We are coming ever closer to the dream of being able to recreate actual organs in the lab for transplantation, and also believe that tissue grown through this method could be used as an alternative to animal testing of chemicals.”

 

And with the restoration of functional hair follicles, maybe my fellow bald brethren could one day get back a full set of hair.

The New World That iPS Cells Will Bring

A stem cell champion was crowned last month. Dr. Takahashi from the RIKEN center in Japan received the prestigious Ogawa-Yamanaka Prize for developing a human iPS cell therapy to treat a debilitating eye disease called macular degeneration. We wrote about the event held at the Gladstone Institutes in a previous blog and saved the juicy insights from Dr. Takahashi’s scientific presentation and her CIRM-exclusive interview for today.  We also put together a two minute video (see below) based on the interview with her as well as with Dr. Deepak Srivastava, Director of the Gladstone Institute of Cardiovascular Disease and Mr. Hiro Ogawa, a co-founder of the Ogawa-Yamanaka Prize.

Dawn of iPS Cells

As part of the ceremony, Dr. Takahashi gave a scientific talk on the “new world that iPS cells will bring”. She began with a historical overview of stem cell research, starting with embryonic stem cells and the immune rejection and ethical issues associated with their use. She then discussed Dr. Yamanaka’s game-changing discovery of iPS cells, which offered new strategies for disease modeling and potential treatments that avoid some of the issues can complicate embryonic stem cells.

Her excitement over this discovery was palpable as she explained how she immediately jumped into the iPS cell field and got her hands dirty. Knowing that this technology could have huge implications for regenerative medicine and the development of stem cell therapies, she made herself a seemingly unattainable promise. “I said to myself, I will apply iPS cells to humans within five years. And I became a woman of her words.”

An iPS cell world

Dr. Takahashi went on to tell her success story, and why she chose to develop an iPS cell therapy to treat a disease of blindess, age-related macular degeneration (AMD). She explained how AMD is a serious unmet medical need. The current treatment involves injections of an antibody that blocks the activity of a growth factor called VEGF. This factor causes an overgrowth of blood vessels in the eye, which does major damage to the cells in the retina and can cause blindness. This therapy however, is only useful for some forms of AMD not all.

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Dr. Masayo Takahashi describing her team’s iPS-based therapy for macular degeneration during the inaugural ceremony for the Ogawa-Yamanaka Prize at The Gladstone Institutes.

She believed she could fix this problem by developing an iPS cell technology that would replace lost cells in the eye in AMD patients. To a captivated crowd, she described how she was able to generate a sheet of human iPS derived cells called retinal pigment epithelial (RPE) cells from a patient with AMD. This sheet was transplanted into the eye of the patient in the first ever iPS cell clinical trial. The transplant was successful and the patient had no adverse effects to the treatment.

While the clinical trial is currently on hold, Dr. Takahashi explained that she and her team learned a lot from this experience. They are currently pursuing additional safety measures for their iPS cell technology to make sure that the stem cell transplants will not cause cancer or other bad outcomes in humans.

Autologous vs. Allogeneic?

Another main topic in her speech, was the choice between using autologous (iPS cells made from a patient and transplanted back into the same patient) and allogeneic (iPS cells made from a donor and then transplanted into a patient) iPS cells for transplantation in humans. Dr. Tahakashi’s opinion was that autologous would be ideal, but not scaleable due to high costs and the amount of time it would take to make iPS cell lines for individual patients.

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iPS cells reprogrammed from a woman’s skin. Blue shows nuclei. Green and red indicate proteins found in reprogrammed cells but not in skin cells (credit: Kathrin Plath / UCLA).

Her solution is to use an arsenal of allogeneic iPS cells that can be transplanted into patients without rejection by the immune system. This may be possible if both the donor and the patient share the same combination (called a “haplotype”) of cell surface proteins on their immune cells called human leukocyte antigens (HLA). She highlighted the work ongoing in Japan to generate a stock of HLA haplotype matched iPS cell lines that could be used for most of the Japanese population.

 Changing the regulatory landscape in Japan

It was clear from her talk that her prize winning accomplishments didn’t happen without a lot of blood, sweat, and tears both at the bench and in the regulatory arena. In a CIRM exclusive interview, Dr. Takahashi further explained how her pioneering efforts to bring iPS cells to patients helped revolutionize the regulatory landscape in Japan to make it faster and easier to test iPS cells in the clinic.

The power of iPS cells changed the Japanese [regulatory] law dramatically. We made a new chapter for regenerative medicine in pharmaceutical law. With that law, the steps are very quick for cell therapy. In the new chapter [of the law] … conditional approval will be given if you prove the safety of the cell [therapy]. It’s very difficult to show the efficacy completely in a statistical manner for regenerative medicine. So the law says we don’t have to prove the efficacy [of the therapy] thoroughly with thousands of patients. Only a small number of patients are needed for the conditional approval. That’s the big difference.”

We were curious about Dr. Takahashi’s involvement in getting these regulatory changes to pass, and learned that she played a significant role on the academic side to convince the Japanese ministry to change the laws.

This law was made in the cooperation with the ministry and academia. That was one thing that had never happened before. Academia means mainly the Japanese society for the regenerative medicine, and I’m a committee member of that. So we talked about the ideal law for regenerative medicine, and our society suggested various points to the ministry. And to our surprise, the ministry accepted almost all of the points and included them into the law. That was wonderful. Usually we are very conservative and slow in changing, but this time, I was amazed how quickly the law has been changed. It’s the power of iPS cells.”

The iPS cell future is now

As a champion stem cell scientist and a leader in regenerative medicine, Dr. Takahashi took the opportunity at the end of the event to emphasize that all scientists and clinicians in the iPS cell therapy field need to consider three things: develop safe protocols for generating iPS cells that become standard practice, understand the patient’s needs by focusing on how to benefit patients the most, and think of iPS cells as a treatment and consider the risk when developing these therapies.

The new world of iPS cells is opening doors onto uncharted territory, but Dr. Takahashi’s wise words provide a solid roadmap for the future success of iPS cell therapies.

Stem cell stories that caught our eye; progress toward artificial brain, teeth may help the blind and obesity

Here are some stem cell stories that caught our eye this past week. Some are groundbreaking science, others are of personal interest to us, and still others are just fun.

More progress toward artificial brain. A team at the RIKEN Institute in Japan has used stem cells in a 3-D culture to create brain tissue more complex than prior efforts and from an area of the brain not produced before, the cerebellum—that lobe at the lower back of the brain that controls motor function and attention. As far back as 2008, a RIKEN team had created simple tissue that mimicked the cortex, the large surface area that controls memory and language.

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The Inquisitr web portal wrote a feature on a wide variety of efforts to create an artificial brain teeing off of this week’s publication of the cerebellum work in Cell Reports. The piece is fairly comprehensive covering computerized efforts to give robots intelligence and Europe’s Human Brain Project that is trying to map all the activity of the brain as a starting point for recapitulating it in the lab.

The experts interviewed included Robert Caplan of Tufts University in Massachusetts who is using 3-D scaffolding to build functional brain tissues that can process electrical signals. He is not planning any Frankenstein moments; he hopes to create models to improve understanding of brain diseases.

“Ideally we would like to have a laboratory brain system that recapitulates the most devastating diseases. We want to be able to take our existing toolkit of drugs and understand how they work instead of using trial and error.”

Teeth eyed as source of help for the blind. Today the European Union announced the first approval of a stem cell therapy for blindness. And already yesterday a team at the University of Pittsburg announced they had developed a new method to use stem cells to restore vision that could expand the number of patients who could benefit from stem cell therapy.

Many people have lost part or all their vision due to damage to the cornea on the surface of their eye. Even when they can gain vision back through a corneal transplant, their immune system often rejects the new tissue. So the ideal would be making new corneal tissue from the patient’s own cells. The Italian company that garnered the EU approval does this in patients by harvesting some of their own cornea-specific stem cells, called limbal stem cells. But this is only an option if only one eye is impacted by the damage.

The Pittsburgh team thinks it may have found an unlikely alternative source of limbal cells: the dental pulp taken from teeth that have be extracted. It is not as far fetched at it sounds on the surface. Teeth and the cornea both develop in the same section of the embryo, the cranial neural crest. So, they have a common lineage.

The researchers first treated the pulp cells with a solution that makes them turn into the type of cells found in the cornea. Then they created a fiber scaffold shaped like a cornea and seeded the cells on it. Many steps remain before people give up a tooth to regain their sight, but this first milestone points the way and was described in a press release from the journal Stem Cells Translational Medicine, which was picked up by the web site ClinicaSpace.

CIRM funds a project that also proposes to use the patient’s own limbal stem cells but using methods more likely to gain approval of the Food and Drug Administration than those used by the Italian company.

Stem cells and the fight against obesity. Of the two types of stem cells found in your bone marrow, one can form bone and cartilage and, all too often, fat. Preventing these stem cells from maturing into fat may be a tool in the fight against obesity according to a team at Queen Mary University of London.

The conversion of stem cells to fat seems to involve the cilia, or hair-like projections found on cells. When the cilia lengthen the stem cells progress toward becoming fat. But if the researchers genetically prevented that lengthening, they stopped the conversion to fat cells. The findings opens several different ways to think about understanding and curbing obesity says Melis Dalbay one of the authors of the study in a university press release picked up by ScienceNewsline.

“This is the first time that it has been shown that subtle changes in primary cilia structure can influence the differentiation of stem cells into fat. Since primary cilia length can be influenced by various factors including pharmaceuticals, inflammation and even mechanical forces, this study provides new insight into the regulation of fat cell formation and obesity.”