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Rejuvenation of Regeneration in the Aging Central Nervous System



From Cell Stem Cell
By Stuart P. Atkinson

Oligodendrocytes precursor cells (OPCs) differentiate into oligodendrocytes with remyelination capabilities which, in the adult central nervous system (CNS), restores conduction, prevents axonal degradation and promotes functional recovery. Reduction in this capacity in aging (Sim et al) leads to demyelinated neurons and axonal degeneration, which is understood to be mediated in part by environmental signals (Hinks and Franklin). This suggests that exogenous factors may be able to reverse this age-associated decline in function, which has now been addressed in an article (Ruckh and Zhao et al) in Cell Stem Cell by researchers in the laboratory of Amy J. Wagers (Howard Hughes Medical Institute) and Robin J.M. Franklin (MRC Centre for Stem Cell Biology and Regenerative Medicine).

In order to examine the impact of environmental factors on remyelination efficiency after spinal cord demyelination, aged mice were joined to isogenic (genetically identical) or congenic (genetically dissimilar) young animals through heterochronic parabiosis (GFPyoung/WTold) (Conboy et al and Villeda et al). Three weeks after joining, the older partner was injected with lysolecithin to induce demyelination in the spinal cord and GFP labelling of the younger mouse allowed the detection of younger partner cells at the site of lesion in the older partner. Analysis of the lesions after 7 and 14 days showed a larger presence of proliferating OPCs (Nkx2.2+ and Ki67+) in the heterochronic old animals over isochronic controls and was associated with a significant increase in the density of CD34+ endothelial cells, previously shown to induce OPC proliferation (Arai and Lo). Further, a larger number of mature oligodendrocytes (Olig2 and CC1) was discovered; so much so that at 21 days post lesion, the prevalence of mature oligodendrocytes in heterochronic-old lesions was equivalent to Olig2+/CC1+ cell densities in the isochronic-young group. Excitingly, the presence of these cells was also associated with an improvement in remyelination in the heterochronic-old animals.

Analysis of oligodendrocyte localisation found that young oligodendrocytes did not localise and engraft at the lesion site in the old animals (no overlap of GFP+ cells and Olig2+ cells) indicating that enhanced remyelination was mediated by endogenous old OPCs, whose differentiation capacity was restored by exposure to a young systemic environment. It was also shown that young OPCs were not functionally impaired by the presence of circulating factors from the old partner, suggesting that the enhancement of OPC differentiation in old animals exposed to a young systemic environment reflects a positive influence of the young environment rather than a dilution of negative inputs from the aged environment. Further analysis of GFP+ cells at the lesion site found them to be largely MAC1+ macrophages with very small numbers of GFP+/CD4+ and GFP+/CD8+ T lymphocytes, GFP+/CD94+ natural killer cells, GFP+/B220+ B cells and GFP+/NIMP-R14+ neutrophils also present.

The innate immune system (principally macrophages) has been previously suggested to stimulate remyelination (Kotter et al and Shechter et al), and analysis of a single young CCR2-deficient mouse (CCR2 being a chemotactic factor for monocytes and macrophages) found a significant reduction in CC1+/Olig2+ cells 21 days post lesion, thereby confirming a role for recruited macrophages/monocytes in remyelination. Analysis of heterochronic parabiotic pairings with CCR2-deficient, GFP-expressing mice as young partners found that the density of mature oligodendrocytes was decreased significantly in lesions of old WT animals paired to young CCR2-deficient animals, as compared with old animals paired with young WT partners. How youthful macrophages accomplish their effect on old lesions was next addressed using an array-based comparison of 97 cytokines in the serum of isochronic-old, heterochronic-old (WT/WT), and heterochronic-old paired with young CCR2-deficient animals (CCR2-/-/WT), which yielded few differences suggesting that modulation of factors within the local microenvironment of the lesion exerted a greater influence on remyelination than alterations in levels of specific circulating factors in the bloodstream.   Interestingly, further analysis found that the phagocytic activity of macrophages was behind their function in promoting OPC function. The efficiency of lipid-rich myelin debris clearance is reflected by the amount of detectable lipid within the lesion area and lipid levels in the lesions of old partners involved in heterochronic parabiosis were similar to those in young isochronic pairs, and were significantly reduced when compared with those in old isochronic pairs, while the enhancement of myelin debris clearance after heterochronic pairing was substantially attenuated in pairings involving CCR2-deficient young partners.

Overall this data suggests that exposing spinal cord lesions of old animals to circulation of factors from a young partner promotes OPC proliferation, reverses the age-associated differentiation block of OPCs, restoring the ability of these cells to form mature, remyelinating oligodendrocytes to levels indistinguishable from those of young animals mediated by the recruitment of monocytes/macrophages which augment the clearance of inhibitory myelin debris. This suggests that as aged OPCs have the ability to function as young OPCs in response to exogenous signals, changes in the aged OPCs are predominantly epigenetic presumably induced by environmental pressures. Further this work may have implications for therapeutic intervention in long-term demyelinating diseases such as multiple sclerosis (MS), by perhaps providing pharmacological targets to stimulate remyelination.


Further Reading

‘The fountain of youth; Choose your partner wisely’



Arai, K., and Lo, E.H. (2009).
An oligovascular niche: cerebral endothelial cells promote the survival and proliferation of oligodendrocyte precursor cells.
J. Neurosci. 29, 4351–4355.

Conboy, I.M. et al (2005).
Rejuvenation of aged progenitor cells by exposure to a young systemic environment.
Nature 433, 760–764.

Hinks, G.L., and Franklin, R.J.M. (2000).
Delayed changes in growth factor gene expression during slow remyelination in the CNS of aged rats.
Mol. Cell. Neurosci. 16, 542–556.

Kotter, M.R. et al (2006).
Myelin impairs CNS remyelination by inhibiting oligodendrocyte precursor cell differentiation.
J. Neurosci. 26, 328–332.

Ruckh JM, Zhao JW et al (2012).
Rejuvenation of regeneration in the aging central nervous system.
Cell Stem Cell. 10(1), 96-103.

Sim, F.J. et al (2002).
The age-related decrease in CNS remyelination efficiency is attributable to an impairment of both oligodendrocyte progenitor recruitment and differentiation.
J. Neurosci. 22, 2451–2459.

Shechter, R. et al (2009).
Infiltrating blood-derived macrophages are vital cells playing an anti-inflammatory role in recovery from spinal cord injury in mice.
PLoS Med. 6, e1000113.

Villeda, S.A. et al (2011).
The ageing systemic milieu negatively regulates neurogenesis and cognitive function.
Nature 477, 90–94.