progenitor cells

Scientists Uncover Common Cell Signaling Pathway Awry in Some Types of Autism

Brain cells grow faster in children with some forms of autism due to distinct changes in core cell signaling patterns, according to research from the laboratory of Anthony Wynshaw-Boris, MD, PhD, chair of the department of genetics and genome sciences at Case Western Reserve University School of Medicine, and a member of the Case Comprehensive Cancer Center. Rapid cell growth can cause early brain overgrowth, a common feature in 20-30% of autistic children. But, the genetics of autistic children vary making it difficult to pinpoint common mechanisms underlying the disease.

“Autism is a complex disorder with multiple genetic and non-genetic factors,” explained Wynshaw-Boris. “Because the causes are diverse, it may help to define a subset of patients that have a common [symptom], in this case early brain overgrowth.”

In a study published in Molecular Psychiatry, Wynshaw-Boris and his colleagues started with skin cell samples from autistic children with enlarged brains and worked backward. Researchers in the laboratory “reprogrammed” donated skin cells to produce cells found in the developing brain including induced pluripotent stem cells and neural progenitor cells. Stem and progenitor cells are important therapeutic tools as they have the potential to grow into a multitude of cell types. The researchers hypothesized that even though the children in the study had different forms of autism, the precursor cells could be used to find common molecular and cellular mechanisms.

The researchers discovered that cells derived from autistic donors grew faster than those from control subjects and activated their genes in distinct patterns. Genes related to cell growth were unusually active, leading to more cells but fewer connections between them. This can cause faulty cell networks unable to properly transmit signals in the brain and enlarged heads during early development.

The researchers identified abnormal genes in the cells grown from autistic donors as belonging to the Wnt signaling pathway. The Wnt genes are critical for cell growth and serve as central players in cell networks, interfacing with multiple signaling pathways. Wynshaw-Boris previously identified the Wnt pathway as related to autism in mouse models of the disease. In a separate study published in Molecular Psychiatry earlier this year, the Wynshaw-Boris laboratory showed mice lacking Wnt genes display autism-like symptoms including social anxiety and repetitive behavior. The researchers could prevent these adult symptoms by treating the mice with medications that activate Wnt signaling in the uterus, during development.

“The Wnt pathway is one of the core developmental pathways conserved from invertebrates to humans. Our studies solidify previous suggestions that this pathway has a role in autism,” said Wynshaw-Boris.

Once they identified the dysfunctional signaling pathway in their reprogrammed autistic samples, the researchers (including the laboratories of Alysson Muotri, PhD at the University of California San Diego and Fred Gage, PhD at the Salk Institute) attempted to correct it by exposing mature nerve cells derived from autistic donors to drug compounds. One drug currently being tested in clinical trials for autism is insulin growth factor 1 (IGF-1). When the researchers added IGF-1 to nerve cells derived from autistic donors, neural networks were reestablished. It is unclear whether the positive effects of IGF-1 were on the Wnt pathway, and the exact compensatory mechanism requires further investigation.

Wynshaw-Boris’s studies in cell culture and mouse models of autism confirm improper Wnt signaling can lead to rapid brain cell growth and brain enlargement in the embryo, resulting in abnormal social behavior after birth. The next step will be to determine which genes are most impacted by Wnt signaling defects during early development, and how these changes result in abnormal behavior. “We would also like to find other drugs or compounds that may slow down the growth of the cells in tissue culture,” said Wynshaw-Boris. Together, these findings may help researchers unravel common ways brain cells can become impaired during early development in carefully chosen subsets of patients and contribute to symptoms across the autism spectrum.

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To make an organ or tissue transplant a success, it has to be accepted by the recipients’ immune system and must have good blood supply from a healthy network of small blood vessels. 

For scientists looking to grow tissues in the lab for transplants these are two big obstacles.

But researchers at the University of Bath could help to overcome the problem with a new way of growing tiny blood vessels, like capillaries, from a patient’s own blood.

Their technique uses gel made from blood cells as a scaffold, on which cells that help maintain blood vessel walls, called endothelial progenitor cells (EPCs), are grown. The team has shown that this can grow those essential small blood vessels.

Not only are these tiny blood vessel connections vital for the survival of transplanted tissue, the risk of rejection is lower because the gel and EPCs come from the patient in the first place. 


Images: Tiago Fortunato, University of Bath

Read the research paper

Clinical Trial Offers Hope to Restore Limb Function in Man with Complete Cervical Spinal Cord Injury

Physicians at Rush University Medical Center became the first in Illinois to inject AST-OPC1 (oligodendrocyte progenitor cells), an experimental treatment, into the damaged cervical spine of a recently paralyzed man as part of a multicenter clinical trial.

Dr. Richard G. Fessler, professor of neurological surgery at Rush University Medical Center, is principal investigator for the Phase 1/2a, multicenter clinical trial involving AST-OPC1 at Rush, one of six centers in the country currently studying this new approach.

Fessler injected an experimental dose of 10 million AST-OPC1 cells directly into the paralyzed man’s cervical spinal cord in mid-August. These injected cells were derived from human embryonic stem cells. They work by supporting the proper functioning of nerve cells, potentially helping to restore the conductivity of signals from the brain to the upper extremities (hands, arms, fingers) in a recently damaged spinal cord.

Interim research results from the trial were announced at the 55th Annual Scientific Meeting of the International Spinal Cord Society (ISCoS), which was held in Vienna, Austria, on September 14-16, 2016.

“Until now, there have been no new treatment options for the 17,000 new spinal cord injuries that happen each year,” says Fessler. “We may be on the verge of making a major breakthrough after decades of attempts.”

The next phase of the clinical research trial will involve a dose of 20 million oligodendrocyte progenitor cells, which is the highest dose being studied in this study involving patients who have recently suffered a complete cervical spinal cord injury.

“These injuries can be devastating, causing both emotional and physical distress, but there is now hope. In the 20 years of my research, we have now reached a new era where we hope to demonstrate through research that a dose of very specially made human cells delivered directly to the injured site can have an impact on motor or sensory function,” says Fessler. “Generating even modest improvements in motor or sensory function can possibly result in significant improvements in quality of life.”

Early research results from the trial were announced at the 55th Annual Scientific Meeting of the International Spinal Cord Society (ISCoS), which is being held in Vienna, Austria, on September 14-16, 2016.

“Our preliminary results show that we may in fact be getting some regeneration. Some of those who have lost use of their hands are starting to get function back. That’s the first time in history that’s ever been done,” says Fessler. “Just as a journey of a thousand miles is done one step at a time, repairing spinal cord injuries is being done one step at a time. And, now, we can say that we’ve taken that first step.”

The clinical trial is designed to assess safety and effectiveness of escalating doses of the special cells (AST-OPC1) in individuals with a complete cervical spinal cord injury. Thus far, three individuals have been enrolled in the study at Rush.
The trial has involved the testing of three escalating doses of AST-OPC1 in patients with subacute, C5-C7, neurologically-complete cervical spinal cord injury. These individuals have essentially lost all sensation and movement below their injury site with severe paralysis of the upper and lower limbs. AST-OPC1 is administered 14 to 30 days post-injury. Patients will be followed by neurological exams and imaging methods to assess the safety and activity of the product.

“In the future, this treatment may potentially be used for peripheral nerve injury or other conditions which affect the spinal cord, such as MS,” says Fessler.

For this therapy to work, the cord has to be in continuity and not severed, according to Fessler. The study seeks male and female patients ages 18 to 65 who recently experienced a complete cervical spinal cord injury at the neck that resulted in tetraplegia, the partial or total paralysis of arms, legs and torso. Patients must be able to start screening within 25 days of their injury, and participate in an elective surgical procedure to inject AST-OPC1 14 to 30 days following injury. Participants also must be able to provide consent and commit to a long-term follow-up study.

The study is funded by Asterias Biotherapeutics, which developed the AST-OPC1 (oligodendrocyte progenitor cells) treatment used in the study, and also in part by a $14.3 million grant from the California Institute for Regenerative Medicine (CIRM).

AST-OPC1 cells are made from embryonic stem cells by carefully converting them into oligodendrocyte progenitor cells (OPCs), which are cells found in the brain and spinal cord that support the healthy functioning of nerve cells. In previous laboratory studies, AST-OPC1 was shown to produce neurotrophic factors, stimulate vascularization and induce remyelination of denuded axons. All are critical factors in the survival, regrowth and conduction of nerve impulses through axons at the injury site, according to Edward D. Wirth III, MD, PhD, chief medical director of Asterias and lead investigator of the study, dubbed “SCiStar.”

Researchers observe stem cell specialization in the brain

Adult stem cells are flexible and can transform themselves into a wide variety of special cell types. Because they are harvested from adult organisms, there are no ethical objections to their use, and they therefore open up major possibilities in biomedicine. For instance, adult stem cells enable the stabilization or even regeneration of damaged tissue. Neural stem cells form a reservoir for nerve cells. Researchers hope to use them to treat neurodegenerative disorders such as Parkinson’s and Alzheimer’s disease. Tübingen researchers led by Professor Olga Garaschuk of the University of Tübingen’s Institute for Physiology, working with colleagues from Yale University, the Max Planck Institute of Neurobiology in Martinsried and the Helmholtz Center in Munich, studied the integration of these cells into the pre-existing neural network in the living organism. The results of their study have been published in the latest edition of Nature Communications.

There are only two places in the brains of adult mammals where stem cells can be found – the lateral ventricles and the hippocampus. These stem cells are generating neurons throughout life. The researchers focused on a stem cell zone in the lateral ventricle, from where progenitors of the nerve cells migrate towards the olfactory bulb. The olfactory nerves which start in the nasal tissue run down to this structure, which in mice is located at the frontal base of the brain. It is there that the former stem cells specialized in the task of processing information on smells detected by the nose. “Using the latest methods in microscopy, we were for the first time able to directly monitor functional properties of migrating neural progenitor cells inside the olfactory bulb in mice,” says Olga Garaschuk. The researchers were able to track the cells using special fluorescent markers whose intensity changes according to the cell’s activity.

The study showed that as little as 48 hours after the cells had arrived in the olfactory bulb, around half of them were capable of responding to olfactory stimuli. Even though the neural progenitor cells were still migrating, their sensitivity to odorants and their electrical activity were similar to those of the surrounding, mature neurons. The mature pattern of odor-evoked responses of these cells strongly contrasted with their molecular phenotype which was typical of immature, migrating neuroblasts. “Our data reveal a remarkably rapid functional integration of adult-born cells into the pre-existing neural network,” says Garaschuk, “and they show that sensory-driven activity is in a position to orchestrate their migration and differentiation as well as their decision of when and where to integrate.”