The Role Of Schwann Cells In Neuropathy

Today's post from news.wustl.edu (see link below) gives more information about the role Schwann cells play in neuropathic problems. We may have to get used to seeing the name Schwann cells because more and more research articles are highlighting their influence on nerve damage and pain. Basically, they are cells which wrap themselves around neurons and form the myelin sheath which protects the nerve. They also play a part in sending nerve signals efficiently but now scientists have found that a build up of toxins in Schwann cells can leak out and disable many of their functions. The idea is that drugs will be developed to inhibit these toxins and thus prevent neural decay. It's complex but gives you an idea of how scientists are studying how nerves work, with the aim of developing efficient treatments in the future. 

New clues to causes of peripheral nerve damage
By Caroline Arbanas March 6, 2013

Anyone whose hand or foot has “fallen asleep” has an idea of the numbness and tingling often experienced by people with peripheral nerve damage. The condition also can cause a range of other symptoms, including unrelenting pain, stinging, burning, itching and sensitivity to touch.

Although peripheral neuropathies afflict some 20 million Americans, their underlying causes are not completely understood. Much research has focused on the breakdown of cellular energy factories in nerve cells as a contributing factor.

Now, new research at Washington University School of Medicine in St. Louis points to a more central role in damage to energy factories in other cells: Schwann cells, which grow alongside neurons and enable nerve signals to travel from the spinal cord to the tips of the fingers and toes.

The finding may lead to new therapeutic strategies to more effectively treat symptoms of this highly variable disorder, the scientists reported March 6 in the journal Neuron.

“We found that a toxic substance builds up in Schwann cells that have disabled energy factories, leading to the same kind of nerve damage seen in patients with neuropathies,” said senior author Jeffrey Milbrandt, MD, PhD, the James S. McDonnell Professor of Genetics and head of the Department of Genetics. “Now, we’re evaluating whether drugs can block the buildup of that toxin, which could lead to a new treatment for the condition.”

The most common cause of peripheral neuropathy is diabetes, which accounts for about half of all cases. The condition also can occur in cancer patients treated with chemotherapy, which can damage nerves.

In the body, Schwann cells wrap tightly around nerve axons, the fibers that relay nerve signals. Graduate student and first author Andreu Viader and colleagues in Milbrandt’s lab studied Schwann cells in mice with genetically disabled mitochondria, or cellular energy factories. Under normal conditions, these mitochondria produce fuel and intermediates of energy metabolism that allow nerve cells to function.

The researchers showed that the crippled mitochondria activated a stress response in the Schwann cells. Instead of synthesizing fatty acids, a key component of Schwann cells, the cells burned fatty acids for fuel.

Over time, inefficient burning of fatty acids by the crippled mitochondria leads to a build up of acylcarnitines, a toxic substance, in the Schwann cells. The researchers found levels of acylcarnitines up to 100-fold higher in these mutant Schwann cells than in healthy Schwann cells.

And the bad news doesn’t end there. Eventually, the toxin leaks out of the Schwann cells and onto the nerve axons. Studying neurons in petri dishes, the researchers showed that acylcarnitines damage nerve axons and disrupt the ability of nerves to relay signals.

“The toxin leaking out of the Schwann cells and onto the adjacent nerve axons causes damage that results in pain, numbness, tingling and other symptoms,” Milbrandt said. “We think that is a likely mechanism to explain the degeneration of axons that is known to occur in peripheral neuropathies.”

The new research suggests that drugs that inhibit the buildup of acylcarnitines may block axonal degeneration. Milbrandt and his team now are evaluating the drugs in mice with disabled Schwann cells to see if they can slow or alleviate the decay of axons.

The research is supported by the National Institutes of Health (NIH) Neuroscience Blueprint Center Core Grant (P30 NS057105), the HOPE Center for Neurological Disorders and the National Institutes of Health (AG13730 and PPG 2P01 HL057278).

Viader A, Sasaki Y, Kim S, Strickland A, Workman CS, Yang K, Cross RW, Milbrandt J. Aberrant Schwann cell lipid metabolism linked to mitochondrial deficits leads to axon degeneration and neuropathy. Neuron. March 6, 2013.

Washington University School of Medicine’s 2,100 employed and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children’s hospitals. The School of Medicine is one of the leading medical research, teaching and patient care institutions in the nation, currently ranked sixth in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children’s hospitals, the School of Medicine is linked to BJC HealthCare.

http://news.wustl.edu/news/Pages/25064.aspx

MEGA CELLS CONTROL GROWTH OF BLOOD PRODUCING CELLS

While megakaryocytes are best known for producing platelets that heal wounds, these "mega" cells found in bone marrow also play a critical role in regulating stem cells according to new research from the Stowers Institute for Medical Research. In fact, hematopoietic stem cells differentiate to generate megakaryocytes in bone marrow. The Stowers study is the first to show that hematopoietic stem cells (the parent cells) can be directly controlled by their own progeny (megakaryocytes).

The findings from the lab of Stowers Investigator Linheng Li, Ph.D., described in the Oct. 19 issue of the journal Nature Medicine, could cause researchers to rethink what they know about the workings of megakaryocytes and potentially lead to new treatments for patients recovering from chemotherapy or organ transplantation.

"Our results suggest that megakaryocytes might be used clinically to facilitate adult stem cell regeneration and to expand cultured cells for adult stem cell transplants," says Meng Zhao, Ph.D., a postdoctoral fellow at Stowers and lead author on the study. Stowers researchers discovered that megakaryocytes directly regulate the function of murine hematopoietic stem cells -- adult stem cells that form blood and immune cells and that constantly renew the body's blood supply. These cells can also develop into all types of blood cells, including white blood cells, red blood cells, and platelets.

Because of their remarkable ability to renew themselves and differentiate into other cells, hematopoietic stems cells are the focus of intense research and have been used to treat many diseases and conditions. The transplantation of isolated human hematopoietic stem cells is used in the treatment of anemia, immune deficiencies and other diseases, including cancer.

Basic research has centered on identifying and characterizing hematopoietic stem cells, however, it is still not clear how hematopoietic stem cells actually work, and how they are regulated because of the complexity of the bone marrow microenvironment. Zhao and his colleagues discovered that as a terminally differentiated progeny, megakaryocytes regulate hematopoietic stem cells by performing two previously unknown functions.

"Megakaryocytes can directly regulate the amount of hematopoietic stem cells by telling the cells when they need to keep in the quiescent stage, and when they need to start proliferating to meet increased demand." Maintaining that delicate balance is important, he adds. "You don't want to have too many or too few hematopoietic stem cells."

These findings are supported by similar research from the laboratory of Paul S. Frenette, Ph.D., at the Albert Einstein College of Medicine, also reported in the Oct. 19 issue of Nature Medicine.

Employing the advanced technology of the Institute's Cytometry, Imaging and Histology centers, the researchers examined the relationship between megakaryocytes and hematopoietic stem cells in mouse bone marrow. In the course of their research, they found that the protein transforming growth factor B1 (TGF-B1), contained in megakaryocytes, signaled quiescence of hematopoietic stem cells. They also found that when under stress from chemotherapy, megakaryocytes signaled fibroblast growth factor 1 (FGF1), to stimulate the proliferation of hematopoietic stem cells.

"Our findings suggest that megakaryocytes are required for the recovery of hematopoietic stem cells post chemotherapy," explains Li. The discovery could provide insight for using megakaryocyte-derived factors, such as TGF-B1 and FGF1, clinically to facilitate regeneration of hematopoietic stem cells, he adds.

Engineering a megakaryocyte niche (a special environment in which stem cells live and renew) that supports the growth of hematopoietic stem cells in culture, is the next step for the researchers. Zhao and his colleagues are also investigating whether a megakaryocyte niche can be used to help expand human hematopoietic stem cells in vitro and stem cell transplantation for patients.

NANOPARTICLES TARGET AND KILL CANCER STEM CELLS THAT DRIVE TUMOR GROWTH

Many cancer patients survive treatment only to have a recurrence within a few years. Recurrences and tumor spreading are likely due to cancer stem cells that can be tough to kill with conventional cancer drugs. But now researchers have designed nanoparticles that specifically target these hardy cells to deliver a drug. The nanoparticle treatment, reported in the journal ACS Nano, worked far better than the drug alone in mice.

Anti-cancer drugs can often shrink tumors but don't kill cancer stem cells (CSCs). Although CSCs might only make up a small part of a tumor, their resistance to drugs allows them to persist. They can then cause a tumor to regrow or spread cancerous cells throughout the body. Xiaoming He and colleagues wanted to develop a nanoparticle system to overcome these cells' defenses.

The researchers packaged the anti-cancer drug doxorubicin into nanoparticles coated with chitosan, a natural polysaccharide that can specifically target CSCs. Once in the acidic environment of the tumor, the nanoparticles degraded and released the drug. Tests on tiny, tissue-like clumps of both normal and cancer stem cells in vitro and on human breast tumors grown in mice showed the therapy successfully killed CSCs and destroyed tumors. The mice showed no obvious side effects.

The authors acknowledge funding from the American Cancer Society and Pelotonia.