Roles of adult neural stem cells may be determined before birth: Study shows potential for scientists to develop new techniques of neural stem cell regeneration and therapy.

Contrary to previous knowledge, a recent study conducted using mice suggests that stem cells in the brain might not be free to specialize into any sort of cell type. The study, led by UC San Francisco researchers, states that these cells have been, in reality, pre-programmed prior to birth to develop into specific kinds of neurons. It was published in Cell.

“This work fundamentally changes the way we think about stem cells,” stated Principal Investigator Arturo Alvarez-Buylla, UCSF Professor of Neurological Surgery, Heather and Melanie Muss Endowed Chair and a Principal Investigator in the UCSF Brain Tumor Research Center and the Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research. “It may be unwelcome news for those who thought of adult neural stem cells as having a wide potential for neural repair. Instead, it looks as if that potential is narrowed down very early during embryonic development. It’s almost as if the embryo is planning for the future.”

Adult stem cells are present in various organs of the body, the majority of which are undifferentiated – having the ability to specialize into various types of cells for tissue growth and regeneration. Most adult stem cells are self-renewing as well – one daughter cell remains undifferentiated after the cell replicates, thereby preserving its potential to differentiate into a different type of cell.

“People have assumed that adult neural stem cells are similarly undifferentiated and self-renewing,” said Alvarez-Buylla, whose lab was the first to identify neural stem cells more than 20 years ago. “We did not see that.”

In the brains of mice and humans, adult neural stem cells are found along the inside walls of cavities known as ventricles. These spaces are filled with cerebrospinal fluid. With the help of superior DNA tagging techniques, the research team followed the developmental patterns of adult neural stem cells in mice, tracing back to their embryonic progenitors.

They discovered that most of the neural stem cells were produced when the mouse embryo was between 13 to 15 days old, which is quite early in embryonic brain development. They then remain inactive until required. Moreover, the study also found that the specific type of neural cell that each of the adult neural stem cell can develop into is determined by its location on the ventricle – which is fixed as early as 11 days of embryonic development.

“So, in this study, we were met with a series of surprises,” expressed Alvarez-Buylla. “Rather than being continually self-renewing, these stem cells are produced at one time during development and then sit quietly until they are reactivated. And when they are reactivated, it turns out that their role in the brain has been partly already determined before birth.”

The researchers were further surprised when they discovered, via DNA tagging, that adult neural stem cells in mice were derived from embryonic neural stem cells, which produce neurons in completely different areas of the brain.

“This means that, somehow, these cells go through a period of neuron production for the embryonic brain and then switch to a different mode and produce cells that get set apart to become adult neural cell progenitors,” explained Alvarez-Buylla. “What is incredible is that the neurons that are produced in the embryo are extremely different than the neurons produced for the adult. So somehow, these embryonic stem cells are switching modes and producing entirely new cell types. This finding has the potential to fundamentally change our picture of the relationship between embryonic and adult stem cells.”

However, Alvarez-Buylla warned that since the study was conducted using mice, inferences to human biology may present certain indirect associations. “However, mouse brains have long been accepted as excellent basic research models for the human brain,” he added.

The study also shows potential for scientists to develop new techniques of neural stem cell regeneration and therapy.

“One implication for humans has to do with the fact that so many different progenitor cells are needed to make the different types of neurons,” he remarked. “While it is true that we are learning how to reprogram adult stem cells to make different types of neurons, this work tells us that if we don’t understand the embryology of the brain, going back to the origins of specific nerve cell types, the likelihood of our being able to use stem cell therapy to repair brain injury is very low.”