[Nikolas]

In a process dubbed “Cellular Alchemy” researchers at Case Western Reserve School of Medicine have succeeded at a technique that converts skin cells to the type of brain cells compromised or destroyed in patients with multiple sclerosis, cerebral palsy and other so-called myelin disorders.

The breakthrough enables on demand, immediate production of myelinating cells, oligodendrocytes, which produce a vital layer of insulation that protects neurons from detirioration and enables the transfer of brain impulses to the rest of the body. In patients with multiple sclerosis, cerebral palsy, and rare genetic disorders called leukodystrophies, myelinating cells are destroyed and cannot be replaced by the body.

Diseases that result in destruction of the oligodendroglial cells include demyelinating diseases such as multiple sclerosis and leukodystrophies. Trauma such as spinal cord injury can also cause demyelination to incur. Cerebral palsy, or periventricular leukomalacia, is caused by the deterioration of the developing oligodendrocytes in the brain areas in and around the cerebral ventricles. In cerebral palsy, spinal cord injury, stroke and possibly multiple sclerosis, oligodendrocytes are thought to be damaged by excessive release of the neurotransmitter glutamate. Oligodendrocyte dysfunction may also be connected to the pathophysiology of schizophrenia and bipolar disorder.

The new technique involves directly converting fibroblasts - an abundant structural cell present in the skin and most organs - into oligodendrocytes. A fibroblast is a type of cell that synthesizes the extracellular matrix and collagen, the architecture of connective tissues and the area around the cells, and it plays a critical role in wound healing. Fibroblasts are the most abundant cells of connective tissue in animals.

"Its 'cellular alchemy,'" explained Paul Tesar, PhD, assistant professor of genetics and genome sciences at Case Western Reserve School of Medicine and senior author of the study.
"We are taking a readily accessible and abundant cell and completely switching its identity to become a highly valuable cell for therapy."

In a process called "cellular reprogramming," the scientists manipulated the levels of three naturally occurring proteins to induce fibroblast cells extracted from skin tissue to become usable precursors to oligodendrocytes called oligodendrocyte progenitor cells.

The team, led by Case Western Reserve researchers and co-first authors Fadi Najm and Angela Lager, rapidly produced billions of these induced oligodendtrocyte precursors. In an even more important step, they showed that induced oligodendrocyte precursors could regenerate new myelin coatings around nerves after being transplanted to mice—a result that gives that hope the technique might be usable to treat human myelin disorders.

When oligodendrocytes become dysfunctional they lose the ability to insulate neurons with myelin layers, thus exposing them to damage and severely crippling the neurons ability to conduct signals. A cure for diseases caused this way would have to regenerate the myelin layer by introducing new, functional oligodendrocytes.

Until now, oligodendrocyte precursor cells and oligodendrocytes could only be obtained from fetal tissue or pluripotent stem cells, which is rare and hard to come by. These techniques have been useful, but with severe limitations.

"The myelin repair field has been hampered by an inability to rapidly generate safe and effective sources of functional oligodendrocytes. The new technique may overcome all of these issues by providing a rapid and streamlined way to directly generate functional myelin producing cells." - explained co-author of the study and myelin expert Robert Miller, PhD, professor of neurosciences at the Case Western Reserve School of Medicine.

This particular study utilized mouse subjects. The next step would have to be proof of concept in human tissue, and testing its safety and feasibility in human patients with myelin disorders. If successful, this approach would provide great hope for patients suffering from one of the disorders caused by myelin instability.

"The progression of stem cell biology is providing opportunities for clinical translation that a decade ago would not have been possible. It is a real breakthrough." - said Stanton Gerson, MD, professor of Medicine-Hematology/Oncology at the School of Medicine and director of the National Center for Regenerative Medicine and the UH Case Medical Center Seidman Cancer Center.

Resoruces:
Transcription factor–mediated reprogramming of fibroblasts to expandable, myelinogenic oligodendrocyte progenitor cells; published April 12th in Nature Biotechnology