Investigators report that when exposed to a young immune system, old oligodendrocytes regain their youthful remyelinating vigor, providing insight into the ability of an older brain to remyelinate.

DR. ROBIN FRANKLIN: “The difficulty is that with pathological studies you only see a snapshot of a dynamic process, so aside from knowing exactly when a lesion started there is no sense of its rate of repair. We don't yet have good enough imaging protocols to follow regeneration of individual lesions in real time. My own view is that aging is the major determinant of remyelination efficiency in MS.”

In the aging nervous system, remyelination after injury is slow and inefficient. But is it because the oligodendrocytes themselves lose capacity as they age, or are they still capable, but inhibited by their surroundings? A new paper in the Jan. 6 issue of Cell Stem Cell convincingly demonstrates the latter, showing that when exposed to a young immune system, old oligodendrocytes regain their youthful remyelinating vigor. The result not only answers a long-standing question in basic myelin biology, but also has important implications for developing treatments for adult demyelinating disorders, including multiple sclerosis.

Showing that one can reactivate the regenerative potential of endogenous cells, even in an aged animal where regeneration is normally impaired “implies that strategies to target endogenous cells can be effective throughout life,” said co-principal investigator Amy J. Wagers, PhD, associate professor of stem cell and regenerative biology at Harvard University.

The experiment was performed in a venerable though unusual model system, called parabiosis, in which the circulatory systems of two mice are surgically joined. Parabiosis has been used to examine related questions for over 100 years, Dr. Wagers said. “The basic question we wanted to address was whether there are systemic influences on regeneration in the spinal cord related to remyelination. To do that, we wanted to be able to expose an old animal to factors in the blood stream in a young animal.”

The alternative, transfusion of blood from one mouse to another, she added, provides a pulsatile and relatively brief exposure, rather than the constant and chronic exposure in the parabiotic system.

After surgically joining a young and old mouse together, Dr. Wagers and colleagues induced a focal demyelination lesion to the older animal's spinal cord by injecting lysolecithin. Young mice were also joined to young mice, and old to old, as controls. One member of each pair was transgenically marked with green fluorescent protein (GFP) to track migrating cells.

They found that the number of proliferating oligodendrocyte precursor cells (OPCs), which give rise to myelin-forming oligodendrocytes, was significantly higher after two weeks in old animals exposed to young ones, versus those exposed to old ones. After three weeks, when remyelination is typically completed in young animals, the prevalence of mature oligodendrocytes in old animals exposed to young ones was the same as in the young/young controls. Myelination in the old animals was significantly better than in the old/old controls.

The GFP staining indicated that enhanced remyelination was not due to an influx of OPCs from the young animals, but rather to the endogenous old OPCs themselves, which had been “rejuvenated” by the exposure to the young immune system. A crucial stimulus came from macrophages from the young partner, which migrated into the lesion in large numbers.

Macrophages have previously been suggested to stimulate remyelination, Dr. Wagers noted, and so to test their role here, they examined remyelination using young mice deficient in the chemokine receptor CCR2, important for macrophage recruitment. Old animals paired with these mice had a partial reduction in the rejuvenating effect, with significantly fewer mature oligodendrocytes. Nonetheless, they fared better than old mice paired with old mice with intact CCR2, possibly indicating the existence of non-macrophage stimulating factors as well.

The beneficial effect of the macrophages appeared to be due at least in part to their ability to clear myelin debris, which was greatest in old mice exposed to young wild-type macrophages, partially impaired for the CCR2-deficient ones, and most impaired for the old wild-type macrophages.

“The notion is that within the debris created by demyelination injury, there are inhibitory factors that suppress the regenerative potential of the endogenous cells,” Dr. Wagers said. “When the macrophages come in, they can clear that out, and that relieves the suppression, and allows for regeneration. The young cells seem to be much more efficient at doing this than the old cells.”

Debris clearance is one difference between young and old cells, “but there are clearly other mechanisms in play,” Dr. Wagers said. The team is currently beginning to look at gene expression arrays for differences between young and old macrophages to get some hints about differences in signaling, for instance.

WILL IT APPLY TO MS?

How applicable are these results to understanding remyelination in multiple sclerosis? While the model used an acute, rather than chronic, demyelination injury, the remyelination process is likely to be the same for both, argued co-principal investigator Robin Franklin, PhD, professor of neuroscience at the MRC Centre for Stem Cell Biology and Regenerative Medicine at the University of Cambridge. “My sense is that the mechanisms are fundamentally the same. It makes most biological sense to have the mechanisms of regeneration independent of the mechanisms of injury.”

Dr. Franklin also argued that decreased remyelination efficiency with aging is likely to be a factor in older MS patients, although hard proof is lacking. “The difficulty is that with pathological studies you only see a snapshot of a dynamic process, so aside from knowing exactly when a lesion started there is no sense of its rate of repair. We don't yet have good enough imaging protocols to follow regeneration of individual lesions in real time. My own view is that aging is the major determinant of remyelination efficiency in MS.”

If these results do in fact apply to MS, Dr. Wagers said, the implications for therapy could be significant. Rather than requiring a transplant to supply new OPCs, drugs may be used to enhance the remyelinating ability of endogenous cells. “I'm a big fan of cell therapy approaches, but they are more challenging than applying a drug,”she said.

Dr. Franklin said there are currently several leads for enhancing OPC differentiation pharmacologically, including an RXR agonist (see Neurology Today April 7, 2011: “New Clues to Remyelination Provide Potential Targets for MS Therapy”: http://bit.ly/zxSAUQ ).

EXPERT COMMENTARY

“This is a tricky experimental technique, and they have handled it masterfully,” said Steven Goldman, MD, PhD, professor of neurology and neurosurgery at the University of Rochester Medical Center in Rochester, NY, who was not involved in the study. “In effect, they reconstituted the immune system of a young individual in the older host.”

“The bottom line was that the parabiotic anastomosis allowed a substantial reconstitution of the myelinogenic capacity of the older animal. This gets to the fundamental question of whether the older brain is able to remyelinate,” and also confirms that the inflammatory response enhances, rather than inhibits, that activity, a longstanding and controversial question in the field, he said. “It's a very nice paper in basic myelin biology.”

That knocking out CCR2 impaired migration and remyelination “really argues it was a very specific chemotactic attraction” of the macrophages to the lesioned area, and supports the prospects for pharmacological intervention further. While still far from the clinic, Dr. Goldman said, “these results give us all sorts of hints in terms of next steps from the experimental standpoint.”

REFERENCE:

• Ruckh JM, Zhao J-W, Wagers AJ, Franklin RJM, et al. Rejuvenation of regeneration in the aging central nervous system. 2012;10(1):96–103.