Regenerating Dead Cells In the Brain with Stem Cells

Neuroscientists at the Université Libre De Bruxelles (ULB) in Belgium have taken a very important step in cell therapy for diseases of the brain. This team generated cortical neurons from embryonic stem cells, which they then used to treat adult with brain problems. This research was recently published in the journal Neuron.

The ULB team was led by Pierre Vanderhaeghen, Kimmo Michelsen and Sandra Acosta (ULB Neuroscience Institute, in collaboration with the laboratory of Afsaneh Gaillard (INSERM/U. Poitiers, France). These results open new perspectives for the repair of damaged cells in the brain and replacing damage neurons.

The cerebral cortex is definitely the most complex and essential structure of our brain. The nerve cells or neurons that compose the cerebral cortex are the basic building blocks that help it do every job that it does. The loss of loss of cortical neurons is the cause of many neurological diseases as a result of stroke, Alzheimer disease, or physical trauma to the brain can seriously compromise brain function.

Previously, these same ULB researchers discovered how to generate cortical neurons in the laboratory cortical neurons from embryonic stem cells. Despite the triumph of these findings, it was completely unclear whether these findings could be translated into a living creature.

Now, the ULB team has successfully tested the use of their laboratory-generated cortical neurons in a living animal. In this study, Vanderhaeghen and others transplanted cortical pyramidal neurons made from embryonic stem cells into the brains of adult mice who had undergone chemically induced brain damage. This experiment cause rather massive neuronal losses in the visual cortex.

Remarkably, the implanted neurons integrated effectively into the brain after injury, but most importantly they could connect with the host brain, and some of them even responded to visual stimuli, like the visual cortex.

Integration only occurred, if the types of implanted neurons were matched to the lesioned area. In other words, since visual cortex neurons were lost, only the implantation of other cortical neurons allowed the cells to properly engraft into the visual cortex. However the grafted neurons displayed long-range patterns of connectivity with the host neurons.

This remains an experimental approach that has, to date, only been successfully performed with laboratory mice. A good deal more much research is required before any clinical application in humans will come to the clinic. Regardless, the success of these experiments combining cell engineering to generate nerve cells in a controlled and unlimited fashion, together with transplantation in to damaged brain, opens new avenues to repair the brain following damage or degeneration, such as following stroke or brain trauma.

Stem-Based Treatment of Stoke

When blood flow to the brain ceases as the result of a blood clot, trauma, or injury, the brain suffers from a shortage of oxygen. Such an incident is known as a stroke and it can result in the death of neurons and the loss of those functions to which the dead neurons contributed. Treatment for stroke is largely supportive, but regenerative treatments that replace the dead neurons would be the most ideal treatment.

A research consortium at Lund University in Lund, Sweden has found that neurons made from induced pluripotent stem cells integrate into the brains of mice that had suffered strokes. This experiment takes a closer step towards the development of a regenerative treatment for strokes.

Strategies for stem cell-based regenerative therapy in neurodegenerative diseases.
Strategies for stem cell-based regenerative therapy in neurodegenerative diseases.

In the aftermath of a stroke, nerve cells in the brain die. At the Lund Stem Cell Center, the research groups of Zaal Kokaia and Olle Lindvall teamed up to develop a stem cell-based method to treat stroke patients.

After a stroke, the cerebal cortex tends to take the bulk of the damage and neuron loss from the cerebral cortex underlies many of the symptoms following a stroke, such a paralysis and speech problems. The method developed by the Lund Institute scientists should make it possible to generate nerve cells for transplantation from the patient’s own skin cells.


First, the Lund team isolated skin fibroblasts from the afflicted mice and used genetic engineering techniques to convert them into induced pluripotent stem cells (iPSCs), which have many of the differentiation capabilities of embryonic stem cells. These iPSC lines were differentiated into cortical neurons, which tend to populate the cerebral cortex. However, transplanting fully differentiated neurons into the brain tend to not work terribly well because the mature neurons are unable to divide and have poor abilities to connect with other cells. Therefore, the neuron progenitor cells that will give rise to cortical neurons are a better candidate for transplantation.

After generating long-term self-renewing neuroepithelial-like stem cells from iPSCs in the laboratory, the Lund group scientists showed that these stem cells could give rise to neural progenitors that expressed the types of genes found in mature cortical neurons. When these neural progenitor cells were transplanted into rats that had suffered strokes, two months after transplantation, the cortically fated cells showed less proliferation and more efficient differentiation into mature neurons with the right shape, size, and structure of cortical neurons and expressed the same proteins as cortical neurons. These tranplanted cells also extended more axons than those cells that were not fated to form cortical neurons. Transplantation of both the cortical neuron-fated and non-cortical neuron-fated cells caused recovery of the impaired function in the stepping test in comparison to controls. At 5 months after stroke, there was no tumor formation and the grafted cells had all the electrophysiological properties of mature neurons and showed full evidence that they had integrated into the existing neural circuitry.

These results are very promising and represent a very early but important step towards a stem cell-based treatment for stroke in patients. Further experimental studies are necessary if these experiments are to be translated into the clinic in a responsible way.

New Brain Stem Cell And Higher Cortical Functions

Neuroscientists at the Scripps Research Institute in La Jolla, California have identified a new stem cell population in the brain that might differentiate into those neurons responsible for higher thinking. Also, by culturing these neurons in the laboratory, scientists might be able to design better treatments for those cognitive disorders, such as schizophrenia and autism that result from abnormal connections among particular brain cells.

This new research also illustrated how neurons in the uppermost layers of the cerebral cortex form during embryonic development of the brain.

Senior author of this work, Ulrich Mueller, professor and director of the Dorris Neuroscience Center at Scripps Research, commented: “The cerebral cortex is the seat of higher brain function, where information gets integrated and where we form memories and consciousness. If we want to understand who we are, we need to understand this area where everything comes together and forms our impression of the world.”

Previously, scientists thought that all cortical neurons, whether they occupied the lower or upper layers of the brain, were derived from the same stem cell; a cell called the radial glial cell (RGC). The fate of neurons were thought to result from when they were born with the earliest neurons migrating only a little and staying close to where they were born (lower layers), and later born neurons migrating further from where they were born (uppermost layers).

Mueller’s research team, however, has identified a neural stem cells that specifically gives rise to neurons that make the upper layers of the cerebral cortex, regardless of the time or place of birth.

Santos Franco, a senior research associate in the Mueller Laboratory said, “Advanced functions like consciousness, thought, and creativity require a lot of different neuronal cell types and a central question has been how all this diversity is produced in the cortex. Our study shows this diversity already exists in the progenitor cells.”

According to Mueller: “The [older] model was that there is a stem cell in the center of the ball that generated the different types of neurons in successive waves. What we now show is that there are at least two different populations of RGCs and potentially more.”

Franco used a mouse strain that he had constructed in which he could track upper-layer neurons as they were born and as they migrated. A marker gene called Cux2 is only expressed by upper-layer neurons, and Franco used an enzyme from bacterial viruses called the Cre protein to flip on a red-glowing protein when Cux2 is expressed.

To their surprise, a population of RGCs flipped on Cux2 at the earliest time of their development (embryonic day 9-10). The problem is that no upper layer neurons exist at this early time in development, which means that these cells are programmed to form upper layer neurons even though no such tissue exists at this time. Non-Cux-2-expressing neurons became lower layer neurons.

Culturing Cux-2-expressing neurons in the laboratory they formed the types of neurons normally found in the upper layer of the brain. Likewise, non-Cux2-expressing neurons formed other types of neurons normally found in the lower layers of the brain.

During development, Cux2-positive stem cells proliferate and self-renew before they differentiate into neurons. Does the birthday of the neuron determine it’s eventual developmental fate? To determine if this is the case, Mueller and his colleagues used a molecule called TCF4 to force premature differentiation of the Cux2-expressing cells. Even under these conditions, the Cux2-expressing cells still formed upper layer neurons.

Thus regardless of their birth date or location of their birth, they still form upper layer neurons. As Mueller puts it, these RGCs have some intrinsic property that determined their cell fate from the start.

This RGC subset is responsible for the huge proliferation of cells required to generate the larger upper-layer cortex found in the brains of primates. With bigger brains, however, comes the risk of disorders from upper-layer neuron connection abnormalities. TO date, researchers have only managed to generate lower-layer neurons from stem cells in the laboratory. According to Mueller, “The opens a door now to try to make the upper-layer neurons, which are frequently affected in psychiatric disorders.”