How Neural Stem Cells Become Neurons and Glia

How do neural stem cells differentiate into neurons or glia? A new paper from researchers at the University of California, Los Angeles (UCLA) seeks to explain this very phenomenon.

Neurons serve as the conductive cells of the nervous system. They transmit electrochemical signals from one neuron to another and provide signals to muscles, glands, and so on. They are responsible for consciousness, thought, learning and memory, and personality.

Despite their immense utility, neurons are not the only cells in the nervous system. Glial cells or just glia support neurons, hold them in place, and supply neurons with oxygen and nutrients and protect them from pathogens.

Glial Cells

When mouse neural stem cells were grown in culture, Wange Lu, associate professor of biochemistry and molecular biology at the Keck School of Medicine, and his colleagues came upon a protein called SMEK1 that promotes the differentiation of neural stem and progenitor cells. SMEK1 also keeps neural stem cells in check by preventing them from dividing uncontrollably.

When Lu and others took a more detailed look at the role of SMEK1, they discovered that it does not work alone, but in concert with a protein called Protein Phosphatase 4 (PP4) to suppress the function of a third protein called PAR3. PAR3 discourages the birth of new neurons (neurogenesis), and PAR3 inhibition leads to the differentiation of neural stem progenitor cells into neurons and glia.

“These studies reveal the mechanisms of how the brain keeps the balance of stem cells and neurons when the brain is formed,” said Wange. “If this process goes wrong, it leads to cancer, or mental retardation or other neurological diseases.”

Neural stem and progenitor cells offer tremendous promise as a future treatment for neurodegenerative disorders, and understanding their differentiation is the first step towards co-opting the therapeutic potential of these cells. This could offer new treatments for patients who suffer from Alzheimer’s, Parkinson’s and many other currently incurable diseases.

This work is interesting. It was published in Cell Reports 5, 593–600, November 14, 2013. My only criticism of some of the thinking in this paper is that neural stem cell lines are usually made from aborted fetuses. I realize that some of these neural stem cell lines come from medical abortions in which the baby had already died, but many of them come from aborted babies. If we are going to use neural stem cells for therapeutic purposes, then we should make them from induced pluripotent stem cells and take them from aborted babies.

Alligator Stem Cells and Tooth Replacement

Mammals usually have one set of baby teeth (also known as milk teeth) and after those are lost, we have one set of adult teeth and these are not replaced if they are lost. This condition is called “monophyodont.” Reptiles and sharks, however constantly replace their teeth. This condition is called “polyphyodont.” Alligators and crocodiles are among one group of reptiles that replace their teeth throughout their lives, and because the development of these creatures has been studied to some extent, it is known that the ability of these creatures to replace their teeth on a regular basis results from a resident stem cell population. Studying that stem cell population more closely might provide clues for tooth replacement in humans.

American Alligator
American Alligator

A research team led by scientists at the Keck School of Medicine professor of pathology Cheng-Ming Chuong at the University of Southern California. Dr. Chuong and his collaborators from around the world have identified unique cellular and molecular mechanisms behind tooth renewals in American alligators.

Chuong explained, “Humans naturally have only two sets of teeth – baby teeth and adult teeth. Ultimately, we want to identify stem cells that can be used as a resource to stimulate tooth renewal in adult humans who have lost teeth. But, to do that, we must first understand how they renew in other animals and why they stop in people.”

Even though humans cannot replace their adult teeth, a tissue called the dental lamina remains, which is known to be crucial for tooth development.

Why are alligators potentially a good model system for tooth replacement in mammals? First author of this study, Ping Wu, explained it this way, “Alligator teeth are implanted in sockets of the dental bone, like human teeth. They have 80 teeth, each of which can be replaced up to 50 times over their lifetime, making them the ideal model for comparison to human teeth.”

Through the use of microscopic imaging techniques, Chuong and others found that each alligator tooth is a complex unit of three components: a functional tooth, a replacement tooth, and the dental lamina, all other which are at different developmental stages.

The tooth units are built to enable a smooth transition from dislodgement of the functional, mature tooth to replacement with a new tooth. Further imaging studies strongly suggested that the dental lamina contains a stem cell population from which new replacement teeth develop.

“Stem cells divide more slowly than other cells, said co-author Randall B. Widelitz, who serves as an associate professor of pathology at USC. Widelitz continued, “The cells in the alligator’s dental lamina behaved like we would expect stem cells to behave. In the future, we hope to isolate those cells from the dental lamina to see whether we can use them to regenerate teeth in the lab.”

The researchers also intend to learn what molecular networks are involved in repetitive renewal and hope to apply the principles to regenerative medicine in the future.

The authors also noted that novel cellular mechanisms are used during the development of the tooth unit. Also, unique molecular signaling speeds growth of replacement teeth when functional teeth are lost.

See P. Wu PNAS 2013; DOI: 10.1073/pnas.12132110.