CIRM grantees convert skin to nerves, a step toward therapies for neurological disease

Last year a group of CIRM grantees at Stanford University directly converted mouse skin cells into neurons, bypassing the need to first convert those cells into an embryonic-like state. Now they've gone a step farther, pulling off the same feat with human cells. They published the work in the May 26 Nature.

Krista Conger at Stanford University blogged about that work , quoting senior author Marius Wernig:

We are now much closer to being able to mimic brain or neurological diseases in the laboratory. We may perhaps even be able to one day use these cells for human therapies.

This past year has seen a number of scientists managing to convert adult cells directly into other adult cell types as we blogged about here. Recent reports about immune rejection of iPS cells makes this work even more interesting because the direct conversion bypasses the need to create iPS cells. As Conger writes:

Interestingly, this direct conversion technique may offer a way around the recently reported rejection of genetically identical iPS cells by laboratory mice. That unexpected finding, which I blogged about a couple of weeks ago, has researchers worried about the potential therapeutic value of the cells. But preliminary investigations suggested that the immune response was targeted at proteins used to make the original cells pluripotent, which shouldn't be an issue with this approach.

That said, Wernig isn't ready to give up on iPS cells. He's part of a CIRM disease team that aims to use genetically modified iPS cells to treat the deadly skin condition epidermolysis bullosa. Here's a link to a summary about that epidermolysis bullosa disease team award, and a link to a videos of the team describing their approach to the CIRM governing board last year.

A.A.

How a stem cell forms a neuron

CIRM grantees at Sanford-Burnham have published another paper using an embryonic stem cell model to understand one of the earliest steps in human nervous system development. (We've blogged about their work before here.)

The group led by Alexey Terskikh has been trying to understand how a group of cells called the neural crest form nerves, skin, bone and muscle. This process has been somewhat mysterious because it happens at such an early stage in development. Scientists can't exactly peer into a woman's womb to see the process unfold.

That's where embryonic stem cells come in. These cells can form all cell types in the body, including neural crest. On their blog, Sanford-Burnham quotes first author on the May 5 Cell Stem Cell study Flavio Cimadamore:

“Neural crest cells are notoriously difficult to study in humans because of their very early and transient nature – a woman is usually not even yet aware of her pregnancy when they start to migrate and differentiate. So here we took advantage of an embryonic stem cell-based model of human neural crest previously developed in our lab to get a better understanding of the molecular pathways that control the differentiation potential of such cells in humans.”

In the current work, the team found that neural crest cells with a gene called SOX2 turned on can go on to form neurons. Those without it can't. That's critical information for people who are trying to understand diseases that arise from neural crest cells that go awry during development. Microphthalmia and CHARGE syndrome are two rare but debilitating childhood diseases that could benefit from knowing more about how the neural crest normally develops.

In the blog entry, Terskikh said:

"We hope this finding will be useful to researchers studying neural crest development and stem cell differentiation.”

CIRM funding: Alexey Turskikh (RS1-004661); Flavio Cimadamore (TG2-01162)
Cell Stem Cell, May 5

A.A.

Antidepressants rev up neural stem cells

Work with neural stem cells suggests that antidepressants such as Zoloft, Prozac and Paxil do their work by encouraging the generation of new brain cells. Happy brain cells, to judge by their effects.

The work was done by British scientists from King's College London's Institute of Psychiatry and published April 12 in in Molecular Psychiatry. A Reuters story discusses the role of new brain cells in depression:

Recent studies have demonstrated that depressed patients show a reduction in a process called neurogenesis -- the development of new brain cells. Researchers believe this reduced neurogenesis may contribute to the debilitating psychological symptoms of depression, such as low mood or impaired memory.

The researchers studied neural stem cells from a part of the brain called the hippocampus. They found that the neural stem cells exposed to Zoloft both produced more stem cells and speeded the development into mature brain cells.

Even more important than seeing the increased stem cells, they figured out which protein in the cell was responsible for the change. The Reuters story quotes Christoph Anacker, a doctorate student who led the study:

"We discovered that a specific protein in the cell, the glucocorticoid receptor, is essential for this to take place," he explained. "The antidepressants activate this protein which switches on particular genes that turn immature stem cells into adult brain cells."

Knowing the molecular basis for the results could help drug companies develop better drugs for treating depression. This study is another example of the value of stem cells in understanding diseases. While some researchers are working towards ways of transplanting new stem cells into the body to treat disease, others are studying stem cells to better understand diseases and develop better, more effective drugs.

Molecular Psychiatry, April 12, 2011

- A.A.

Stem cells reveal elusive developmental steps, origins of disease

Our colleagues at Sanford-Burnham Medical Research Institute have a post today on their excellent blog about work by CIRM grantee Alexey Turskikh, published in a recent issue of PLoS ONE. The teams work is another example of how embryonic stem cells can help scientists understand early events in development.

The team has been interested in a group of cells called the neural crest, which eventually form nerves, skin, bone and muscle in the developing embryo. If scientists could understand this important developmental step they could also understand diseases that result when those steps go awry. The problem is that they can't very well monitor the process in a developing human.

That's where embryonic stem cells come in. The team developed a method of maturing embryonic stem cells into neural crest cells. Sanford-Burhnam writes:

With this method, Dr. Terskikh’s group and others will now be able to better study what defines human neural crest stem cells, how they migrate during development, how they differentiate into other cell types, and the mechanisms that guide these processes. What’s more, producing workable quantities of neural crest stem cells in the laboratory might allow scientists to generate more of the tissues that they become – including clinically-relevant cell types like skin cells or neurons.

According to Dr. Maurer, one of the study’s co-authors, “This research allows for fast and easy access to an important developmental structure and one of the best examples of a particular stage in development – the epithelial-mesenchymal transition (EMT). Since EMT is now a hot topic in tumorigenesis and cancer progression, these cells might help us better understand the molecular mechanisms governing that process. ”

There's a long path from find the cells to developing cures, but you don't get to the end of a race without taking the first step.

CIRM Funding: Alexey Turskikh (RS1-00466-1)

- A.A.

Stem cell progress on brain awareness week

This week marks Brain Awareness Week, with events worldwide to bring people up to speed on brain research. I went to the cool search tool on the Dana Foundation web site and found that several CIRM grantees are hosting events this week. That makes sense, given that roughly a quarter of our funding goes to neuronal diseases. (You can see charts of CIRM stem cell research funding allocations here. The charts are slightly out of date — stay tuned for some updates in the next month.)

Brain diseases are seen as a big challenge for stem cell therapies, in part because the brain itself is such a complex web of neurons. Simply replacing a few lost neurons won't necessarily replicate the lost connections. We have a story discussing some of those issues and describint innovative approaches CIRM grantees are taking to developing new cures for brain diseases.

The good news is that some CIRM grantees are learning that stem cells can be coaxed to form the support cells in the brain that nourish neurons. These support cells could be what provide a therapy for diseases such as ALS, MS, stroke and spinal cord injury. Other grantees are using stem cells in the lab to test new drugs for Parkinson's disease.

A group at UC Davis is attempting to use the body's own mesenchymal stem cells to preserve unaffected neurons in people with Huntington's disease. This technique won't bring back lost cells, but saving additional cells from dying off could prevent some of the terrible side effects of the disease.

Another team of CIRM grantees at UC Irvine found that at least in rodents, stem cells were able to repair some memory loss due to Alzheimer's disease. This work is a long way from treating humans, but still provides hope for people who have lost loved ones to this devastating disease. Here's a video we produced about that work:



We've produced several other videos about CIRM's brain related research:

• Fred H. Gage talks about using embryonic stem cells to model neuronal disease
• Spinal Cord Injury: Progress and Promise in Stem Cell Research
• Huntington's Disease: Progress and Promise in Stem Cell Research
• Parkinson's Disease: Progress and Promise in Stem Cell Research
• Spotlight on ALS seminar
• Spotlight on Huntington's disease seminar
• Spotlight on Alzheimer's disease seminar
• Spotlight on Batten disease seminar
• Spotlight on Parkinson's disease seminar

 - A.A.

Between Mice and Men, a New Type of Stem Cell

Humans and other non-human primates stand out from their fellow mammals in many ways, but notably by having one particularly oversized area of the brain. This area, the outer subventricular zone (OSVZ) feeds migrating neurons to the neocortex the seat of sensory perception, spatial reasoning, conscious thought and language. Scientists always assumed the OSVZ must have its own source of stem cells if, in the developing brain, it is supplying neurons for such a broadly vital area of the human brain. They have now found them.

Arnold Kriegstein’s team at UCSF used discarded fetal tissue to monitor cellular activity at various stages of development using a new labeling and tracking technique. They found the OSVZ to be a hub of cell proliferation. The newly found stem cell type goes through asymmetrical division producing a copy of itself and a daughter cell that is further along the path to becoming a neuron. That cell then goes through many rounds of symmetrical division producing many copies that can all then go on to become the desired neuronal cells needed in the neocortex.

A press release issued by UCSF on May 24 noted that the understanding provided by this model could shed light on many developmental brain diseases such as autism and schizophrenia. Kreigstein is quoted saying this understanding is critical:

“If we’re going to understand how these disorders develop, we have to better understand how the human and primate cerebral cortex develops.”

Understanding this developmental pathway will also inform efforts to direct neural stem cells to become the replacement cells of choice for various therapies.

D.G.

Nature, March 25 2010
CIRM Funding: Arnold Kriegstein (RC1-00346-1), Jan Lui (T1-00002)

Protein protects brain from damage, may prevent neurodegenerative diseases

Researchers at the University of California, San Diego and the Salk Institute for Biological Studies have found a protein that protects the brain from the kind of damage that can lead to Parkinson's disease. This protein, called Nurr1, has a long history in Parkinson's disease research. People who carry a mutation in the gene are prone to developing the disease. The new work explains how the protein prevents Parkinson's disease and could also help researchers find ways of treating of preventing the disease. The protein was especially important in two types of cells that protect and support the brain's neurons -- called microglia and astrocytes. In these cells, Nurr1 works with other proteins to limit inflammation after an immune response. Without it, these support cells produced toxic by-products that damaged the nerves in a way that could lead to Parkinson's disease or other neurodegenerative diseases.

Cell: April 3, 2009
CIRM funding: Beate Winner and Fred H. Gage (RC1-00115), Christian Carson (T3-00007), Leah Boyer (T1-00003)

Related Information: Press release, University of California, San Diego, Salk Institute for Biological Studies, Gage bio

iPS Cells Mature into Functional Motor Neurons

Researchers at the University of California, Los Angeles have matured induced pluripotent stem (iPS) cells into what appear to be normal motor neurons. This work shows that iPS cells can mature into cells that appear similar to those derived from human embryonic stem cells – a finding that has important implications for people hoping to create new therapies based on iPS cells. These cells are created by reprogramming adult cells back into a pluripotent state that resembles embryonic stem cells. One question has been whether these reprogrammed cells have the same capacity as embryonic stem cells to turn into mature, functioning cell types. This work shows that, at least for motor neurons, iPS and embryonic stem cells have the same capacity to form mature cells. Scientists can study these motor neurons in the lab to learn about – and find cures for – diseases such as amyotrophic lateral sclerosis (Lou Gehrig’s Disease), spinal muscle atrophy or spinal cord injury.

Stem Cells:February 23, 2009 (online publication)
CIRM funding: William Lowry (RS1-00259)

Related Information: Broad Stem Cell Research Center, Lowry lab page

Embryonic Stem Cells Generate Model for ALS

Researchers at the Salk Institute for Biological Sciences have grown embryonic stem cells into the motor neurons and support cells that underlie amyotrophic lateral sclerosis (ALS). Also known as Lou Gherig’s Disease, ALS has no cure and no effective treatment. In this disease, the motor neurons slowly degenerate leaving a person paralyzed. Why the neurons die is not known, however the support cells called astrocytes have long appeared to play a role. Now researchers have coaxed embryonic stem cells to form the motor neurons and astrocytes in a lab dish to better understand their relationship in ALS. What they learned is that astrocytes containing a mutation associated with ALS killed off the neighboring motor neurons. This mutation is in a gene that makes a protein whose normal role is to protect the body from damaging oxygen free radicals. When the group grew these same cells in the presence of a powerful anti-oxidant, the motor neurons survived. In addition to understanding the biology of ALS, the group thinks they could use this system to screen drugs that may be able to treat ALS.



Cell Stem Cell: December 4, 2008
CIRM funding: Fred H. Gage (RC1-00115)

Related Information:Press release, Salk Institute for Biological Sciences, Gage  bio

True Location of Brain Stem Cells Discovered

Researchers at UC, Irvine identified the true location of adult stem cells in the brain. Previous studies indicated that in mammals, adult neural stem cells originate in a region of the brain called the subventricular zone. In this study, the team found evidence that stem cells exist only in a region called the ependymal layer, which is adjacent to the subventricular zone. They also coaxed the ependymal stem cells to divide in adult rats displaying Parkinson's Disease-like symptoms. This work raises the possibility that manipulating cells of the ependymal cell layer could lead to stem cell therapies for neurological diseases.

Neuroscience: July 11, 2008
CIRM funding: Darius Gleason (T1-00008)

Related Information: UC, Irvine press release, Sue and Bill Gross Stem Cell Research  Center

Proteins Found that Guide Neuron Migration in Brain

Researchers at UC, San Francisco discovered that membrane proteins that form cell to cell connections also have an important role in controlling how neurons migrate in the brain. Understanding neuronal migration is a critical aspect of cell therapy in the nervous system, as replacement cells will need to be directed to their appropriate site of action. This research project is also an example of how funding work in one field moves along work in another. The membrane proteins highlighted in this report had previously been identified in some cancers, and these new observations in neurons provide rationale for targeting them in cancer therapy.

Nature: August 23, 2007
CIRM funding: Laura Elias (T1-00002)

Related Information: Press release, UCSF Institute for Regeneration Medicine

Neural Stem Cell Repair Mechanism in the Brain Revealed

Researchers at UC, San Francisco found that proteins involved in the generation of neurons early in development also help neural stem cells produce neurons after birth. Furthermore, the researchers identified a self-repair mechanism in the brain that relies on these neural stem cells. Understanding how endogenous neural stem cells repair and remodel a mature brain is critical to successful stem cell therapy.

Cell: December 15, 2006
CIRM-funded author: Chay Kuo (T1-00002)

Related Information: Press release, UCSF Institute for Regeneration Medicine