The Transformation of Ordinary Skin Cells into Functional Brain Cells


A paper in Nature Biotechnology from research groups at Case Western Reserve School of Medicine describes a technique that directly converts skin cells to the specific type of brain cells that suffer destruction in patients with multiple sclerosis, cerebral palsy, and other so-called myelin disorders. This particular breakthrough now enables “on demand” production of those cells that wrap or “myelinate” the axons of neurons.

Myelin is a sheath that wraps the extension of neurons called the axons. Neurons are the conductive cells that initiate and propagate nerve impulses. Neurons contain cell extensions known as axons that connect with other neurons. The nerve impulse runs from the base of the cell body of the neurons, down the axon, to the neuron to which it is connected. An insulating myelin sheath that surrounds the axon increases the speed at which nerve impulses move down the axon. When this myelin sheath is damaged, nerve impulse conduction goes awry as does nerve function. For example, patients with multiple sclerosis (MS), cerebral palsy (CP), and rare genetic disorders called leukodystrophies, myelinating cells are destroyed are not replaced.

neuron

The new technique discussed in this Nature Biotechnology paper, directly converts skin cells called fibroblasts, which are rather abundant in the skin and most organs, into oligodendrocytes, the type of cell that constructs the myelin sheath in the central nervous system.

Oligodendrocyte

“Its ‘cellular alchemy,'” explains 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.”

Tesar and his group used a technique called “cellular reprogramming,” to manipulate the levels of three naturally occurring proteins to induce the fibroblasts to differentiate into the cellular precursors to oligodendrocytes (called oligodendrocyte progenitor cells, or OPCs).

OPCs

Led by Case Western Reserve researchers and co-first authors Fadi Najm and Angela Lager, Tesar’s research team rapidly generated billions of these induced OPCs (called iOPCs). They demonstrated that iOPCs could regenerate new myelin coatings around nerves after being transplanted to mice—a result that offers hope the technique might be used to treat human myelin disorders.

Demyelinating diseases damage the oligodendrocytes and cause loss of the insulating myelin coating. A cure for these diseases requires replacement of the myelin coating by replacement oligodendrocytes.

Until now, OPCs and oligodendrocytes could only be obtained from fetal tissue or pluripotent stem cells. These techniques have been valuable, but have distinct limitations.

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

Even though this initial study used mouse cells, the next critical next step is to demonstrate feasibility and safety of human cells in a laboratory setting. If successful, the technique could have widespread therapeutic application to human myelin disorders.

“The progression of stem cell biology is providing opportunities for clinical translation that a decade ago would not have been possible,” says 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. “It is a real breakthrough.”