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by Deborah Franklin
Treating myelin injuries and tracking brain cell development to rescue the littlest patients.
Rowitch’s team improved remyelination repair in mouse models of demyelination using a small molecule Wnt inhibitor. An injection of lysolecithin removed oligodendrocytes and myelin, while sparing the axons. In the mice that received the Wnt inhibitor along with the injection, remyelination was more rapid than in mice that received no inhibitor with the lysolecithin. Note the thicker black myelin around the axons on the electron microscopy image on the right.
Babies born prematurely—as much as three months too soon—have a better chance of surviving than they did just a decade ago. But they face serious neurological problems that HHMI investigator David Rowitch sees too often in his clinical rounds at the University of California, San Francisco (UCSF). Using tissue from a new neonatal brain bank, he is gathering clues to devise treatments for brain-injured babies and perhaps also for adults with multiple sclerosis.
“We routinely take care of babies in the United States that are born at about six months of gestation, weighing about a pound,” says Rowitch, a neonatologist. “About 10–20 percent will develop cerebral palsy—an inability to move and talk normally—and as many as 50 percent will develop learning, cognitive, or behavioral problems.” At least some of those problems, Rowitch says, stem from damage to the protective myelin coating that insulates nerve cell axons in the “white matter” of the baby’s brain.
“Therapies to limit the damage or enhance repair don’t exist,” Rowitch says. Answering even basic questions about the developing human brain has been tough because of the lack of autopsied tissue from young children available for study.
Last summer, however, Rowitch and colleagues published two studies, conducted using tissue from the neonatal and pediatric brain bank that he helped establish at UCSF in 2009 with HHMI support, that offer clues to nerve cell repair as well as human brain development.
In earlier work, Rowitch and postdoc Stephen Fancy had noticed that white matter injuries in some premature babies look similar to the damaged patches of myelin in multiple sclerosis. Closer study of brain bank specimens revealed why: In both cases, myelin-making cells known as oligodendrocytes and the progenitor cells that give rise to them (known as OPCs) rush in to repair the initial injury. Mysteriously, they don’t complete their task.
“The obvious question is, why aren’t these cells—which are all showing up at the right time in the right place—finishing the job they are almost hardwired to do?” Rowitch says. “We figured there had to be some inhibitor present, right there in the area of the lesion.”
Reporting in Nature Neuroscience in June 2011, the team suggests one plausible reason for the blocked repair: overactivation of the Wnt pathway, as measured by expression of the gene AXIN2. Wnt is well known as an important, complex signaling pathway involved in the development of most organ systems throughout the body. When the scientists injected an experimental drug that slows degradation of the Axin2 protein directly into patches of damaged myelin in mice, it inhibited Wnt, and the OPCs lining the wound rapidly differentiated into healthy, myelin-making oligodendrocytes. The myelin injuries healed 30 percent faster than similar injuries in untreated mice.
Image: Stephen Fancy / Rowitch lab