Inhibition of Gli1 Enhances Remyelination Abilities of Endogenous Stem Cell Populations


Nerve cells, otherwise known as neurons, have long extensions called axons. Nerve impulses travel down these axons, away from the cell body towards another neuron that is connected to the neuron. The axons of some neurons are insulated with a special substance called myelin the layer of myelin that surrounds the axon. This “myelin sheath” acts as a protective covering composed of protein and lipids.

myelin_sheath

Axons can vary in length from anywhere to 1 millimeter or less to 1 meter. Sometimes, axons are bundled together to form nerves that transmit electrical nerve impulses across the body.

While myelin protects and insulates axons, it also enhances the speed at which nerve impulses are transmitted through the axon. Axons without myelin sheaths conduct nerve impulses continuously throughout the axon. However, myelinated axons have small, uncovered gaps in the myelin sheath called nodes of Ranvier. Myelinated axons can only conduct nerve impulse at the nodes of Ranvier. Consequently, the nerve impulse jumps from node to node, greatly increasing the speed of nerve impulse conduction.

nodes_of_ranvier

If myelin is damaged, the speed of nerve impulse transmission slows substantially. Multiple sclerosis is one example of a disease that causes systematic loss of the myelin sheath. Inflammatory demyelinating diseases also cause progressive damage and loss of the myelin sheath. Regenerating the myelin sheath in these patients is one of the goals of regenerative medicine.

A good deal of data tells us that endogenous remyelination does occur. Unfortunately, this process is overwhelmed by the degree of demyelination in these diseases. A stem cell population called the parenchymal oligodendrocyte progenitor cells and endogenous adult neural stem cells in the brain are known to remyelinate demyelinated axons.

The Salzer laboratory at the New York Neuroscience Institute examined the ability of a specific adult neural stem cell population to remyelinate axons. These stem cells expressed the transcription factor Gli1.

Salzer and his team showed that this subventricular zone-specific group of neural stem cells were efficiently recruited to demyelinated portions of the brain. This same neural stem cell population was never observed entering healthy axon tracts. This finding shows that these cells seem to specialize in making new myelin sheaths for damaged axon tracts.

Since these neural stem cells expressed Gli1, and since there are drugs that can inhibit Gli1 activity, Salzer’s group wanted to show that Gli1 was a necessary factor for neural stem cell activity. Surprisingly, differentiation of these neural stem cells into oligodendrocytes (which make myelin and remyelinate axons) is significantly enhanced by inhibition of Gli1.

A specific signaling pathway called the hedgehog pathway is known to activate Gli1 and other members of the Gli gene family. However, when the hedgehog pathway in these neural stem cells was completely inhibited, it did not have the same effect and Gli1 inhibition. This suggests that Gli1 is doing more than responding to the hedgehog pathway in these neural stem cells.

Salzer and his colleagues showed that Gli1 inhibition improved myelin deposition in an animal model of experimental autoimmune encephalomyelitis; an inflammatory demyelination disease. Thus, inhibition of Gli1 activity in this preclinical model system increase regeneration of the myelin sheath in demyelinated neurons.

This work elegantly showed that endogenous neural stem cells that can remyelinate axons are present and can be activated by inhibiting Gli1. Furthermore, this activation will nicely enhance the therapeutic capacity of these endogenous cells. This potentially identifies a new therapeutic avenue for the treatment of demyelinating disorders.

This work was published in Nature. 2015 Oct 15;526(7573):448-52. doi: 10.1038/nature14957.

Skull Suture Stem Cells Can Heal Birth Defect and Facial Injuries


A research group from the University of Southern California (USC) School of Dentistry have identified a new stem cell population that is responsible for a particular birth defect and might someday help treat wounded soldiers, accident victims and other patients recover from disfiguring facial injuries.

“This has a lot more implication than what we initially thought,” said Yang Chai, a lead researcher on the study at the Herman Ostrow School of Dentistry of USC. “We can take advantage of these stem cells not only to repair a birth defect, but to provide facial regeneration for veterans or other people who have suffered traumatic injury.”

According to Chai, treatments of human patients that utilize the new stem cell population he and his colleagues identified could become available within the next five to 10 years, but it must pass through the intense hurdles of clinical trials with human patients.

In their mouse studies, Chai and his team noticed a stem cell population that expresses the transcription factor Gli1+. These Gli1+ stem cells appear within the tissues that eventually fuse the craniofacial bones together. However, in mice that have a shortage or even absence of the Gli1+ stem cells, the skull bones prematurely fused together to cause “craniosynostosis,” a birth defect that locks the skull into a small structure can cannot accommodate the growing brain and can hinder brain development. Chai and his colleagues also found that these Gli+ stem cells are activated when the skull is injured. Therefore, they transplanted Gli1+ stem cells into injured mice, and within weeks, it was clear that the Gli1+ stem cells had migrated to the injured parts of the skull and were repairing those damaged areas.

“It is a very minimal procedure to just cut off a strip of bone instead of cutting the entire calvaria [skull-cap],” Chai said. A stem cell treatment “will truly restore the normal anatomy, which will then be able to respond to the continuous brain growth and the patient can live a normal life.”

These findings also have upset the bone development apple cart, according to Hu Zhao, the first author of this publication. “Before our findings, people just assumed the bones all around the body are the same,” Zhao said. “We are now showing that they are all totally different, that they have a different source of stem cells and a different healing mechanism.”

The discovery of these Gli1+ stem cells and their ability to regenerate craniofacial injuries might mean that physicians will be able to use them to treat people who have suffered disfiguring facial injuries and infants diagnosed with craniosynostosis through biological means instead of multiple, high-risk surgeries.

Presently, the surgeons, unknowingly, were destroying the regenerative stem cells that could potentially help the patient when they operated on craniosynostosis patients. During a typical craniosynostosis surgery, doctors break the skull into multiple pieces, staple them together and then discard the suture tissues as waste. Zhao said the procedure, intended to aid brain growth, actually interferes with healing because the Gli1+ stem cells are lost.

According to Chai, a biological approach that transplants Gli1+ stem cells into targeted areas could give infants with craniosynostosis the flexibility that they need for their brains to grow normally. For those patients who have suffered head trauma or facial disfigurement, the Gli1+ stem cells could repair fractured or injured areas.

Chai acknowledges the need to conduct additional experiments before such a treatment is tested in clinical trials with patients.

“One of our ideas is that we could probably use those healthy sutures and the healthy pieces from them and transplant them on the injured sides,” Zhao said.