Cranking it Up to Eleven: Heightened Growth of Neural Stem Cells Linked to Autism-like Behavior

Autism is not one single disease but a suite of many, which is why researchers have long struggled to understand its underlying causes. Often referred to as the Autism Spectrum Disorders, autism has been linked to multiple genetic and environmental factors—different combinations of which can all result in autism or autistic-like behavior.

Could an unusual boost in neural stem cell growth during pregnancy be linked to autistim-like behavior in children?

Could an unusual boost in neural stem cell growth during pregnancy be linked to autitism-like behavior in children?

But as we first reported in last week’s Weekly Roundup, scientists at the University of California, Los Angeles (UCLA) have identified a new factor that can occur during pregnancy and that may be linked to the development of autism-like behavior. These results shed new light on a notoriously murky condition.

UCLA scientist Dr. Harley Kornblum led the study, which was published last week in the journal Stem Cell Reports.

In it, Kornblum and his team describe how inflammation in pregnant mice, known as ‘maternal inflammation’ caused a spike in the production of neural stem cells—cells that one day develop into mature brain cells, such as neurons and glia cells. This abnormal growth, the team argues, led to enlarged brains in the newborn mice and, importantly, autism-like behavior such as decreased vocalization and social behavior, as well as overall increase in anxiety and repetitive behaviors, such as grooming. As Kornblum explained in a news release:

“We have now shown that one way maternal inflammation could result in larger brains and, ultimately, autistic behavior is through the activation of the neural stem cells that reside in the brain of all developing and adult mammals.”

However, Kornblum notes that many environmental factors may cause inflammation during pregnancy—and the inflammation itself is not thought to directly cause autism.

“Autism is a complex group of disorders, with a variety of causes. Our study shows a potential way that maternal inflammation could be one of those contributing factors, even if it is not solely responsible, through interactions with known risk factors.”

These known risk factors include genetic mutations, such as those to a gene called PTEN, which have been shown to increase one’s risk for autism.

Further research by Kornblum’s team further clarified the connection between inflammation and neural stem cell overgrowth. Specifically, they noticed a series of chemical reactions, known as a molecular pathway, appeared to stimulate the growth of neural stem cells in the developing mice. The identification of pathways such as these are vital when exploring new types of therapies—because once you know the pathway’s role in disease, you can then figure out how to change it.

“The discovery of these mechanisms has identified new therapeutic targets for common autism-associated risk factors,” said Dr. Janel Le Belle, the paper’s lead author. “The molecular pathways that are involved in these processes are ones that can be manipulated and possibly even reversed pharmacologically.”

These findings also support previous clinical findings that the roots of autism likely begin in the womb and continue to develop after birth.

One key difference between this work and previous studies, however, was that most studies point to irregularities in the way that neurons are connected as a key factor that leads to autism. This study points to not just a network ‘dysregulation,’ but also perhaps an overabundance of neurons overall.

“Our hypothesis—that one potential means by which autism may develop is through an overproduction of cells in the brain, which then results in altered connectivity—is a new way of thinking about autism.”

Advances in the fields of stem cell biology and regenerative medicine have given new hope to families caring for autistic loved ones. Read more about one such family in our Stories of Hope series. You can also learn more about how CIRM-funded researchers are building our understanding of autism in our recent video: Reversing Autism in the Lab with help from Stem Cells and the Tooth Fairy.

Building a Blueprint for the Human Brain

How does a brain blossom from a small cluster of cells into nature’s most powerful supercomputer? The answer has long puzzled scientists, but with new advances in stem cell biology, researchers are quickly mapping the complex suite of connections that together make up the brain.

UCLA scientists have developed a new system that can map the development of brain cells.

UCLA scientists have developed a new system that can map the development of brain cells.

One of the latest breakthroughs comes from Dr. Daniel Geschwind and his team at the University of California, Los Angeles (UCLA), who have found a way to track precisely how early-stage brain cells are formed. These findings, published recently in the journal Neuron, shed important light on what had long been considered one of biology’s black boxes—how a brain becomes a brain.

Along with co-lead authors and UCLA postdoctoral fellows Drs. Luis de la Torre-Ubieta and Jason Stein, Geschwind developed a new system that measures key data points along the lifetime of a cell, as it matures from an embryonic stem cell into a functioning brain cell, or neuron. These new data points, such as when certain genes are switched on and off, then allow the team to map how the developing human fetus constructs a functioning brain.

Geschwind is particularly excited about how this new information can help inform how complex neurological conditions—such as autism—can develop. As he stated in a news release:

“These new techniques offer extraordinary promise in the study of autism, because we now have an unbiased and genome-wide view of how genes are used in the development of the disease, like a fingerprint. Our goal is to develop new treatments for autism, and this discovery can provide the basis for improved high-efficiency screening methods and open up an enormous new realm of therapeutic possibilities that didn’t exist before.”

This research, which was funded in part by a training grant from CIRM, stands to improve the way that scientists model disease in a dish—one of the most useful applications of stem cell biology. To that end, the research team has developed a program called CoNTEXT that can identify the maturity levels of cells in a dish. They’ve made this program freely available to researchers, in the hopes that others can benefit. Said de la Torre-Ubieta:

“Our hope is that the scientific community will be able to use this particular program to create the best protocols and refine their methods.”

Want to learn more about how stem cell scientists study disease in a dish? Check out our pilot episode of “Stem Cells in your Face.”

Stem cell stories that caught our eye: need for mature fat, Down syndrome, autism and those sweet pup faces

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.

Embryonic stem cells and that sweet puppy face. Could altered stem cells give our pups those floppy ears and adorable faces? Research from Humboldt University in Berlin suggests that is the case. They speculate that when people began to domesticate wild animals they were unwittingly breeding for smaller adrenal glands that are responsible for the “fight-or-flight” syndrome. But those glands arise from a group of stem cells in the developing embryo, the neural crest, that is also responsible for many other aspects of the animal including parts of the skull and the ears.

Annika, a member of the author's "pack," shows the floppy ears and narrow face of domestication. The seat on the furniture could be another clue.

Annika, a member of the author’s “pack,” shows the floppy ears and narrow face of domestication. The seat on the furniture could be another clue.

Researchers have noted since Darwin’s time that these signs of “domestication syndrome” with its floppy ears and narrow faces carry across a broad range of domestic animals. The German team said that the genetic alterations of neural crest stem cells could explain this “hodge-podge of traits.”

The research was published in the journal Genetics and got wide pick up with a fun piece on Mashable and a bit more detail about the science in Pacific Standard Magazine.

Stress might make fat go rogue. It is not something dieters will want to hear, but in order to stay healthy your fat stem cells need to mature into adult fat tissue. When they don’t fat can accumulate at high levels in the bloodstream and within existing cells. A team at Boston University suggests that stress plays a role in how the body processes fat by inhibiting the maturation of fat stem cells. They identified two proteins that act as relay switches to regulate the fat stem cells. That signaling pathway now becomes a target for discovering drugs that might improve our handling of fat, even in times of stress. The team published their work in the Journal of Biological Chemistry and HealthCanal picked up the university’s press release.

Support cells linked to Down syndrome. CIRM-funded researchers at the University of California, Davis have found that the errors in nerve development in Down syndrome may be caused by abnormal functioning of the cells that are supposed to support them, the glial cells. The team started by reprogramming skin cell samples from people with Down syndrome into iPS type stem cells. They then matured those cells in two batches, one into neurons and one into glial cells. The nerves did not seem different from normal nerves but the glial cells produced an abnormally high level of a particular protein. When they mixed the two cell types together, that protein appeared to kill off part of the nerves.

What is intriguing, when they treated the mixed cells with a simple antibiotic the nerve damage did not occur. If the protein only has its negative impact on the developing brain, the finding opens up the possibility of preventive treatment for women who find their fetus has the third chromosome distinctive of Down syndrome. The researchers published their findings in Nature Communication and Science Daily ran a story on the work.

Pros and cons of the large autism trial. Using stem cells to try to treat autism provokes a lot of raw emotion in our field. I frequently field questions from desperate mothers wanting to know where they can take the umbilical cord stem cells they have stored in a freezer to treat their child with autism. I tell them about some of the controversies about this treatment and the need for more data before we know how to use the cells right, if there is any chance they can help at all. The Simons Foundation Autism Research Initiative published a well-balanced analysis of the first large clinical trial trying to answer those questions.

The piece has a skeptic rightfully noting that the type of stem cells in cord blood cannot make replacement cells for the poorly functioning nerve cells in people with autism. It also discusses the possibility that those stem cells might stimulate the person’s own cells to make some of the needed repairs. The trial, which will randomly assign patients to stem cell therapy or no therapy, is being led by Duke University’s Joanne Kurtzenburg, who is described by one outside expert as “the right person to do this.” She is a well-known leader in the field and I would love to have some data to share with parents.

CIRM hosted a group of international experts in autism to look at ways stem cells could foster therapies in autism that produced this report. One of the main suggestions was to use iPS type stem cells to model the disease as shown in this video.

Don Gibbons