A Piece of the MS Puzzle

March 4, 2015—Roughly 2.3 million people worldwide live with multiple sclerosis (MS), a disease that affects the central nervous system. Assistant Professor of Biology Jeffrey Huang investigates complex interactions in the brain in the hope of improving therapies for MS patients.

Multiple sclerosis is an immune-mediated disease in which the immune system attacks cells in the central nervous system. Supported by funding from the National Multiple Sclerosis Society, Huang and his researchers are looking to answer the question, “Once you have MS, what do you do to prevent it from progressing?” Huang said.

Huang’s research focuses on the disease’s effects on the brain, particularly two types of brain cells—oligodendrocytes and neurons. Oligodendrocytes are glial cells that help “ensure the survival of neurons by providing various nutrients and factors,” Huang explained. Neurons send signals throughout the brain via axons, the part of the neuron where electrochemical transmission occurs. “In order for the axon to send its signal rapidly, it has an insulating membrane called myelin—that’s what’s made from oligodendrocytes,” Huang said.

When an individual has MS, the immune system destroys myelin and oligodendrocytes through persistent inflammation. As myelin and oligodendrocytes are damaged, axons can no longer send signals as quickly, which can eventually lead to neuron degeneration.

Multiple sclerosis is characterized by periods of relapsing and remitting. During a relapse, there is a flare of inflammation that destroys myelin. During remission, there is less aggressive inflammation and brain cells try to repair themselves. But there are very few brain cells that can regenerate, Huang says.

“The fortunate thing about oligodendrocytes is that they can regenerate,” Huang explained.

That’s where Huang’s research comes in. Huang and his team of postdoctoral, graduate, and undergraduate students are investigating ways to promote and enhance myelin repair, which requires them to delve into the process of how oligodendrocytes regenerate and make myelin.

Oligodendrocytes precursor cells (OPCs) are widely distributed throughout the brain and make up seven to eight percent of the cells in the brain. “Following myelin destruction, the [OPCs] become active and come into the [damaged] area,” Huang said. “They make oligodendrocytes or become oligodendrocytes and then make myelin.”

Huang and his team investigate the extrinsic and intrinsic signals that change OPCs into oligodendrocytes. OPCs must first be activated and proliferated into the damaged area and then, through differentiation, possibly become oligodendrocytes. “Activation and differentiation turn out to be modulated by different aspects of inflammation,” Huang said. This process is also affected by cells called classically activated macrophages (M1) and alternatively activated macrophages (M2). M1 activates the process of OPC proliferation, but actually inhibits OPC differentiation, whereas M2 promotes differentiation and suppresses inflammation. To promote oligodendrocytes creation and myelin repair, there must be a balance of both M1 and M2.

“In multiple sclerosis, in chronic stages of the disease, there’s a deficiency in M2 response,” Huang explained. “If you could increase M2 response or harness the beneficial factors of M2 that are involved in stimulating differentiation or suppressing inflammation, then those are potential therapeutic targets,” he continued.

“We’re starting to identify factors that are in the inflammatory environment that support differentiation. It turns out that one factor we identified recently, which is really exciting, is an M2-derived factor.”

Huang has tested this factor, a protein derived from M2, in mice with myelin damage. The factor was able to enhance and accelerate regeneration. “We have now started to examine this particular protein in a more clinically relevant model,” Huang said.

Scientists are examining many avenues for treating and curing MS—preventing inflammation flare ups, promoting myelin regeneration, and protecting neurons. Huang’s research in myelin regeneration, or remyelination, would help create options were none exist. “Ideally that would be great. There are no drugs right now that actively promote regeneration, but this is an active area of research by many people.”

—Elizabeth Wilson