Journal Club: Friday, February 3, 2012

Amir Touray (Tisch MS) presented the following article in Journal Club.

Article title: Rejuvenation of Regeneration in the Aging Central Nervous System

Reference: J. Ruckh, J. Zhao, J. Shadrach, P. van Wijngaarden, T. Nageswara Rao, A. Wagers, and R. Franklin.
Cell Stem Cell - 6 January 2012 (Vol. 10, Issue 1, pp. 96-103)

Remyelination in adult mammals is a regenerative process in which new myelin sheath tissue is produced from adult stem cells. This process restores dielectric insulation and therefore improves conduction by demyelinated axons, prevents further degeneration of naked axons, and promotes functional recovery from neurological disorders stemming from myelin loss. Stimulation of remyelination in demyelinating diseases such as MS could alleviate the major underlying causes of disability -- impaired conduction by demyelinated neurons and axonal degeneration. However, like most mammalian tissues, the CNS experiences declining efficiency of regeneration with increasing age. Reduced remyelination in aged animals occurs in part due to changes in the environmental signals regulating remyelination, but also reflects epigenetic changes within aging oligodendrocyte precursor cells (OPCs), which decrease their ability to differentiate into remyelinating oligodendrocytes.

To examine the impact of the systemic environment on remyelination efficiency after spinal cord demyelination, the authors of the present paper surgically joined aged mice to isogenic or congenic young animals through heterochronic parabiosis. Three weeks after animals were parabiotically joined, demyelination was induced in the spinal cord of the old partner by focal injection of the demyelinating toxin lysolecithin. To control for possible effects of the parabiotic condition itself, heterochronic animals were always compared to isochronic pairs (young mice joined to young partners, or old mice joined to old partners). Although heterochronic animal pairs experienced less remyelinating activity than isochronic young pairs, the aged partner in the heterochronic pair underwent greater remyelination than the isochronic old pairs, to a statistically significant degree. Overall, it was found that exposure to a youthful systemic environment enhances remyelination in aged animals (and specifically enhances the remyelinating function of endogenous, aged OPCs), that monocytes from the young partner are critical for rejuvenation of remyelination, and that young macrophages augment myelin debris clearance, further enhancing remyelination. Although the data are significant, their potential utility in the research and treatment of MS is limited by the fact that unlike MS, the animal model used in the present study, lysolecithin, is not a model of autoimmune demyelination, and therefore the results may be orthogonal to mechanisms by which demyelination occurs and remyelination is hindered in MS.