Brain Stem Cells Reprogrammed to Treat Mice With Multiple Sclerosis

Scientists at the University of Rochester Medical Center and the University at Buffalo have published a technique for harvesting and using a patient’s own stem cells to treat Multiple Sclerosis. This same technique could potentially find additional applications for treating other rare, fatal children’s diseases.

Cells in the central nervous system capable of generating nerve impulses are known as neurons. Neurons have long extensions called axons and nerve impulses are propagated down the axon, away from the central body of the neuron. In order for nerve impulses to move much faster through the axons of the central nervous system than they normally would, many neurons have a an insulating sheath called the “myelin sheath” that surrounds the axon. Without a myelin sheath, nerve impulses move at as speeds of about 1 meter per second. With a myelin sheath, nerve impulses move much faster; faster than 120 meters per second.

In the peripheral nervous system, the myelin sheath is made by cells called Schwann cells. In the central nervous system, the myelin sheath is made by cells called oligodendrocytes. Oligodendrocytes are derived from “oligodendrocyte progenitor cells” or OPCs. This New York research group isolated and directed stem cells from the human brain to become oligodendrocytes. They injected these cultured OPCs into the brains of mice that were born without the ability to make myelin. 12 weeks later, the implanted cells had become oligodendrocytes and had coated more than 40 percent of the brain’s neurons with myelin. This same group had used a similar strategy in two papers published in Cell Stem Cell and Nature Medicine. However, this recent reported a four-fold increase in myelination.

Steven Goldman, research team leader and chair of the Department of Neurology at the University of Rochester Medical Center, noted that these implanted OPCs are presently the best candidates for treating patients with multiple sclerosis and other myelin disorders. Goldman noted, “These cells migrate more effectively throughout the brain, and they myelinate other cells more quickly and more efficiently than any other cells assessed thus far. Now we finally have a cell type that we think is safe and effective enough to propose for clinical trials.”

Fraser Sim, the first author of the paper, who is an assistant professor of Pharmacology and Toxicology at the University at Buffalo, and Rochester graduate student Crystal McClain, ran extensive analyses of gene activity in different types of stem cells. These data led to the conclusion that stem cells that express a protein called CD140a on their surfaces seemed to be most likely to become OPCs. Sim said, “Characterizing and isolating the exact cells to use in stem cell therapy is one key to ultimately having success. You need to have the right cells in hand before you can even think about getting to a clinical trial to treat people. This is a significant step.”

In order to make this experiment work, the research team needed to know how to direct brain stem cells into becoming OPCs. They turned to a decade of research by the Goldman lab that has tested the effects of many growth factors, small molecules and other factors on brain stem cell differentiation. The group used two specific growth factors, BMP4, which directs brain stem cells to become support cells called astrocytes, and Noggin, which drives the astrocyte-like cells to become OPCs. These cultured cells are very responsive to chemical cues from their local environment. It is important to select the right type of stem cell, but it is also just as important to generate a milieu that has the proper molecular signals to produce the type of cell needed for a particular treatment.

This current work focuses on the creation of myelin, and while myelin loss plays a large role in multiple sclerosis, but myelin loss also plays a central role in other childhood disorders. For example, cerebral palsy, diabetes, high blood pressure, and some cases of stroke also include myelin loss. While Goldman’s team has had previous success remyelinating the brains of mice born without myelin, these new results identify a specific subset of cells that appear to be the most efficient yet at producing myelin and improve the hope of developing cell therapy as a way to treat these diseases.

Multiple Sclerosis treatment might involve the injection of stem cells to create myelin in the brains of patients. In fact, one of the authors of this paper, Martha Windrem, has developed methods to inject cells into the brain so that they will migrate throughout a large swath of the brain, laying down myelin on neurons as they go. Sim suggests that another approach might “involve using certain medications to turn on these cells already present in the brains of patients and thereby create new myelin. The use of the new techniques described in this work will permit us to better understand how human cells behave in the brain and help us predict which medications may be successful in the treatment of myelin loss.”