Old cells need not apply: how a stem cell’s age can impact potential treatments

Getting older is a normal, at times existential, part of life. The outward changes are abundant and noticeable: thinning of the hair, greying of the hair, and added lines to the face. There are also changes that happen that are not so abundantly clear in terms of outward appearance: slowing of healing time for bone fractures and a gradual loss of bodily function. The process of aging poses one very fundamental question — Could understanding how stem cells age lead to a greater understanding of how diseases develop? More importantly, could it guide the approach towards developing potential treatments? Two different studies highlight the importance of evaluating and understanding the process of aging in stem cells.

The first study, led by Dr. Michael Fehlings, looked at the impact of donor age in relation to stem cell therapies for spinal cord injuries (SCI). Dr. Fehlings, with a team of investigators from the University of Toronto and Krembil Research Institute, University Health Network, used an adult rat model to look at how cells derived from young vs. old stem cells affected tissue regeneration and recovery after a spinal cord injury.

Some rats with a SCI received cells derived from stem cells in the umbilical cord blood, which are considered “young” stem cells. The other rats with a SCI received cells derived from stem cells in the bone marrow, which are considered “old” stem cells. The results showed, ten weeks after treatment, that rats given the “young” stem cells exhibited a better recovery in comparison to those given the “old” stem cells.

In a press release, Dr. Fehlings stated that,

“Together, this minimally invasive and effective approach to cell therapy has significant implications on the treatment of traumatic cervical SCI and other central nervous system injuries. These results can help to optimize cell treatment strategies for eventual use in humans.”

The full results to this study were published in Stem Cells Translational Medicine.

The second, separate study, conducted by Dr. Stephen Crocker at UConn Health, looks at brain stem cells in people with multiple sclerosis (MS), a neurodegenerative disease caused by the inflammation and destruction of the insulation around the nerves, also known as myelin. Problems with insulation around the nerves can prevent or complicate the electrical signals sent from the brain to the body, which can lead to problems with walking or other bodily movements.

Drawing of a healthy nerve cell with insulation (left) and one damaged by multiple sclerosis (right). Image courtesy of Shutterstock

Dr. Crocker and his team found that brain stem cells in patients with MS look much older when compared to the brain stem cells of a healthy person around the same age. Not only did these brain stem cells look older, but they also acted much older in comparison to their healthy counterparts. It was also discovered that the brain stem cells of MS patients were producing a protein that prevented the development of insulation around the nerves. What is more remarkable is that Dr. Crocker and his team demonstrated that when this protein is blocked, the insulation around the nerves develops normally again.

In a press release, Dr. Valentina Fossati, a neurologist at the New York Stem Cell Foundation who evaluated these brain stem cells, stated that,

“We are excited that the study of human stem cells in a dish led to the discovery of a new disease mechanism that could be targeted in much-needed therapeutics for progressive MS patients.”

The complete study was published in the Proceedings of the National Academy of Sciences (PNAS).

Why having a wrinkled brain is a good thing

Brain_01

We normally associate wrinkles with aging, such as wrinkled skin. But there’s one organ that is wrinkled right from the time we are born. It’s our brain. And new research shows those wrinkles are not a sign of age but are, in fact, a sign of just how large and complex our brains are.

The wrinkles, according to U.C. Santa Barbara (UCSB) postdoctoral scholar Eyal Karzbrun, are vital to our development because they create a greater surface area giving our neurons, or brain nerve cells, more space to create connections and deliver information.

In an article in UCSB’s Daily Nexus, Karzbrun says while our knowledge of the brain is increasing there are still many things we don’t understand:

“The brain is a complex organ whose organization is essential to its function. Yet it is ‘assembled by itself’. How this assembly takes place and what physics come into play is fundamental to our understanding of the brain.”

Eyal Karzbrun

Eyal Karzbrun: Photo courtesy UCSB

Karzbrun used stem cells to create 3D clusters of brain cells, to better understand how they organize themselves. He said brains are like computers in the way they rely on surface area to process information.

“In order to be computationally strong and quick, what your brain does is take a lot of surface area and put it in a small volume. The cerebral cortex, which occupies most of the volume in your brain, has a unique architecture in which neurons are layered on the outer surface of the brain, and the bulk of the brain is composed of axons, [or] biological wire which interconnect the neurons.”

Karzbrun says gaining a deeper understanding of how the brain is formed, and why it takes the shape it does, may help us develop new approaches to treating problems in the brain.

 

Salk Scientists Unlock New Secrets of Autism Using Human Stem Cells

Autism is a complex neurodevelopmental disorder whose mental, physical, social and emotional symptoms are highly variable from person to person. Because individuals exhibit different combinations and severities of symptoms, the concept of autism spectrum disorder (ASD) is now used to define the range of conditions.

There are many hypotheses for why autism occurs in humans (which some estimates suggest now affects around 3.5 million people in the US). Some of the disorders are thought to be at the cellular level, where nerve cells do not develop normally and organize properly in the brain, and some are thought to be at the molecular level where the building blocks in cells don’t function properly. Scientists have found these clues by using tools such as studying human genetics and animal models, imaging the brains of ASD patients, and looking at the pathology of ASD brains to see what has gone wrong to cause the disease.

Unfortunately, these tools alone are not sufficient to recreate all aspects of ASD. This is where cellular models have stepped in to help. Scientists are now developing human stem cell derived models of ASD to create “autism in a dish” and are finding that the nerve cells in these models show characteristics of these disorders.

Stem cell models of autism and ASD

We’ve reported on some of these studies in previous blogs. A group from UCSD lead by CIRM grantee Alysson Muotri used induced pluripotent stem cells or iPS cells to model non-syndromic autism (where autism is the primary diagnosis). The work has been dubbed the “Tooth Fairy Project” – parents can send in their children’s recently lost baby teeth which contain cells that can be reprogrammed into iPS cells that can then be turned into brain cells that exhibit symptoms of autism. By studying iPS cells from individuals with non-syndromic autism, the team found a mutation in the TRPC6 gene that was linked to abnormal brain cell development and function and is also linked to Rett syndrome – a rare form of autism predominantly seen in females.

Another group from Yale generated “mini-brains” or organoids derived from the iPS cells of ASD patients. They specifically found that ASD mini-brains had an increased number of a type of nerve cell called inhibitory neurons and that blocking the production of a protein called FOXG1 returned these nerve cells back to their normal population count.

Last week, a group from the Salk Institute in collaboration with scientists at UC San Diego published findings about another stem cell model for ASD that offers new clues into the early neurodevelopmental defects seen in ASD patients.  This CIRM-funded study was led by senior author Rusty Gage and was published last week in the Nature journal Molecular Psychiatry.

Unlocking clues to autism using patient stem cells

Gage and his team were fascinated by the fact that as many as 30 percent of people with ASD experience excessive brain growth during early in development. The brains of these patients have more nerve cells than healthy individuals of the same age, and these extra nerve cells fail to organize properly and in some cases form too many nerve connections that impairs their overall function.

To understand what is going wrong in early stages of ASD, Gage generated iPS cells from ASD individuals who experienced abnormal brain growth at an early age (their brains had grown up to 23 percent faster when they were toddlers compared to normal toddlers). They closely studied how these ASD iPS cells developed into brain stem cells and then into nerve cells in a dish and compared their developmental progression to that of healthy iPS cells from normal individuals.

Neurons derived from people with ASD (bottom) form fewer inhibitory connections (red) compared to those derived from healthy individuals (top panel). (Salk Institute)

Neurons derived from people with ASD (bottom) form fewer inhibitory connections (red) compared to those derived from healthy individuals (top panel). (Salk Institute)

They quickly observed a problem with neurogenesis – a term used to describe how brain stem cells multiply and create new nerve cells in the brain. Brain stem cells derived from ASD iPS cells displayed more neurogenesis than normal brain stem cells, and thus were creating an excess amount of nerve cells. The scientists also found that the extra nerve cells failed to form as many synaptic connections with each other, an essential process that allows nerve cells to send signals and form a functional network of communication, and also behaved abnormally and overall had less activity compared to healthy neurons. Interestingly, they saw fewer inhibitory neuron connections in ASD neurons which is contrary to what the Yale study found.

The abnormal activity observed in ASD neurons was partially corrected when they treated the nerve cells with a drug called IGF-1, which is currently being tested in clinical trials as a possible treatment for autism. According to a Salk news release, “the group plans to use the patient cells to investigate the molecular mechanisms behind IGF-1’s effects, in particular probing for changes in gene expression with treatment.”

Will stem cells be the key to understanding autism?

It’s clear that human iPS cell models of ASD are valuable in helping tease apart some of the mechanisms behind this very complicated group of disorders. Gage’s opinion is that:

“This technology allows us to generate views of neuron development that have historically been intractable. We’re excited by the possibility of using stem cell methods to unravel the biology of autism and to possibly screen for new drug treatments for this debilitating disorder.”

However, to me it’s also clear that different autism stem cell models yield different results, but these differences are likely due to which populations the iPS cells are derived from. Creating more cell lines from different ASD subpopulations will surely answer more questions about the developmental differences and differences in brain function seen in adults.

Lastly, one of the co-authors on the study, Carolina Marchetto, made a great point in the Salk news release by acknowledging that their findings are based on studying cells in a dish, not actual patient’s brains. However, Marchetto believes that these cells are useful tools for studying autism:

“It never fails to amaze me when we can see similarities between the characteristics of the cells in the dish and the human disease.”

Rusty Gage and Carolina Marchetto. (Salk Institute)

Rusty Gage and Carolina Marchetto. (Salk Institute)


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Timing Matters: Slowly Dividing Stem Cells Lead to Small Brains

One hundred billion nerve cells working together empowering us to see, walk, think, speak, remember: the human brain is a stunning machine. Even more stunning is its formation in the growing fetus. It starts with a set of neural, or brain, stem cells in the early embryo. Then with each cell division, more and more cells emerge and specialize to perform various brain functions. All the while, some of those “daughter” cells remain uncommitted, staying in their neural stem cell form in order to keep a steady cell supply to build the brain. With all these 100,000,000,000 cells needing to be assembled in a precise way,  it’s amazing that our brains work at all.

Microcephaly

MRIs of a healthy individual (left) and a patient with microcephaly (right). Credit: PLoS Biol 2(5): e134

Suffer the children
Well, sometimes they don’t. For about 25,000 babies born in the U.S. each year, the brain doesn’t grow the way it should, leading to microcephaly, a disorder characterized by an abnormally small head (micro=small; cephaly=head). These babies have a range of symptoms including speech delays, seizures, mental retardation and balance difficulties.

Preventing microcephaly first requires understanding why this devastating condition leads to a smaller brain size. On Thursday, a Duke research team reported in Neuron that they have the answer: stem cells dividing too slowly.

In 2010, the team, led by Debra Silver, an assistant professor of molecular genetics and microbiology at the Duke University School of Medicine, found that mice lacking one of two copies of the Magoh gene showed a reduced brain size much like what’s seen in human microcephaly. Their study showed that the genetic defect upset the normal ratio of neural stem cells to neurons (nerve cells) in the brain. But how?

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Slowly dividing neural stem cells generate aberrant stem cells and neurons. Credit: Louis-Jan Pilaz, Duke University

That’s where this new data comes into play. They found that many neural stem cells in mice lacking one copy of the Magoh gene divided at a slower rate, taking up to three times longer than cells with both copies of Magoh. Using specialized microscopes, the team observed the cells in real time and noticed that the slowly dividing cells were more likely to specialize into neurons rather remain in a stem cell state. On top of that, these neurons died off more readily. Silver described the results of this double-whammy of defects in a Duke University press release:

“It’s really a combination that helps explain the microcephaly. On one hand, you’re really not making enough new stem cells, and if you don’t have enough stem cells you can’t make enough neurons in the brain. On the other hand, some neurons do get made, but a lot of them die.”

Proving their point
To back up this claim, the team treated healthy mice with drugs that lengthen the time it takes for a cell to divide. Sure enough, an unusually high number of neural stem cells from those mice specialized into neurons and then succumbed to an early death.

From Silver’s perspective, this discovery doesn’t just provide a foothold in understanding (and maybe in even one day treating) microcephaly, it could be a fundamental insight for human developmental disorders in general:

This study shows that the time it takes for a stem cell to divide matters during brain development, But beyond microcephaly, I think it’s going to be relevant for thinking about how stem cell dysfunction can change the repertoire of other cells in the body.