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.”

DC Court Says that Stem Cells are Drugs

On the 23rd of July, 2012, the US District Court in Washington DC acknowledged the right of the Food and Drug Administration (FDA) to regulate clinical therapies that are made from the patient’s own processed stem cells. This case answered the question, “Does the court agree with the FDA that stem cells are drugs?”

According to the judge, the FDA is right and stem cells cultured outside the body are drugs. This ruling upholds the injunction brought by the FDA against Regenerative Sciences, the Broomfield, Colorado-based clinic that offers the Regenexx stem cell treatment procedure.

The Regenexx procedure uses mesenchymal stem cells that are isolated from patients’ bone marrow. These stem cells are then processed and injected back into the patients to treat joint pain. The FDA has labeled this procedure the “manufacturing, holding for sale, and distribution of an unapproved biological drug product.” In August 2010, the FDA ordered Regenerative Sciences to stop offering the treatment, since they were offering a drug without FDA approval

According Nature magazine science reporter, David Cyanoski, investigations by the FDA that led to the injunction showed that there were flaws in the cell processing protocol that violated the FDA’s regulations that refer to “adulteration.” These regulations are meant to ensure the safety of patients who receive the therapy.

Not surprisingly, academics are praising the decision and a shot across the bow of any enterprising physician who wants to offer stem cell treatments. For example, Jeanne Loring, a regenerative-medicine scientist at the Scripps Research Institute in La Jolla, California, has said that this court decision will send a warning to others who want to offer unapproved stem-cell treatments. In her words: “So many people want to start these companies. They say, ‘FDA? What FDA?’.”

Chris Centeno, the medical director of Regenerative Sciences and one of two majority shareholders, told Nature that he plans to appeal against the ruling. Centeno has replied to the ruling in an internet book entitled “The Stem Cells They Do Not Want You To Have.” Centeno’s main objection during the trial was that the ‘Regenexx’ procedure does not significantly modify the mesenchymal stem cells before they are reinjected into the patient. Therefore, the procedure should be considered a routine medical procedure. The company also argued that because all the processing work is done in Colorado, the procedure should be subject to state law, rather than to regulation by the FDA.

Unfortunately for Centeno, the Ninth Circuit court disagreed with both arguments. According to the court: “the biological characteristics of the cells change during the process.” This and other considerations mean that the cells are more than “minimally manipulated,” which makes them a drug a subject to regulation by the FDA. .

University of Minnesota bioethicist Leigh Turner, agrees with the court on this one. Turner noted: “It is much too simplistic to think that stem cells are removed from the body and then returned to the body without a ‘manufacturing process’ that includes risk of transmission of communicable diseases,” he says. “Maintaining the FDA’s role as watchdog and regulatory authority is imperative.”

The FDA injunction only applies to one of the Regenexx stem-cell products; the Regenexx-C procedure. In this procedure, the bone marrow mesenchymal stem cells are processed for 4–6 weeks. The Regenexx-C procedure will still be available, since after the 2010 injunction, the company moved its treatment location to an affiliated Cayman Island clinic.

Centeno plans to continue providing the other three procedures; Regenexx-SD, Regenexx-AD, and Regenexx-SCP, for joint pain, in the United States. In those treatments, the cells are reinjected within one-two days. Centeno claims that those cells are “minimally manipulated”, and that the FDA sees them as the “practice of medicine” and “has no issues” with them.

According the Nature’s David Cyanoski, until July 25th of this year, a graphic on the Regenerative Sciences website claimed that these three other procedures were “FDA approved.” However, the FDA has not approved these three procedures, and Centeno was not able to provide documentation to support his claims that the agency views the three treatments as outside its purview. This graphic was removed from the Regenexx website after Nature’s enquiries.

Stem-cell ethics and regulation expert, Doug Sipp, who is at the RIKEN Centre for Developmental Biology in Kobe, Japan, is concerned that this ruling will simply drive entrepreneurs to move their stem cell clinics outside the United States to avoid regulation. Indeed, Regenerative Sciences has done just that by setting up their Regenexx-C procedure in the Cayman Islands. According to Sipp, “Other US stem-cell outfits have close ties with partner clinics in Mexico and other neighboring countries, which are traditionally regulatory havens for other forms of fringe medicine as well. I suppose it will be business as usual in such places,”
We will have more to say about this in the days to come, but for now, this is it.