Radioactive brain cells reveal potential path to recovery in multiple sclerosis

Tracking changes in trace amounts of a radioactive isotope of carbon in brain cells can retrospectively reveal the rate of cell division in the human brain. This technique has now been employed in brain tissue of multiple sclerosis patients and uncovered a surprising potential to regenerate lost tissue.

Isabel Hofman

Multiple sclerosis, or MS, is an incurable and progressive inflammatory brain disease that can ultimately lead to extensive nerve damage and loss of brain function. Brains of MS patients are characterised by a reduction of brain tissue and by distinctive lesions called plaques or shadow plaques.

The group of Jonas Frisén at the department of Cell and Molecular Biology at KI in Solna employed an innovative new way to study these MS brain regions. They recruited help from an unassuming bystander – the carbon atoms in the brain cells’ DNA. Earth’s atmosphere contains three forms of carbon: ¹²C – the most stable and abundant; ¹³C – another neutral and stable form; and ¹⁴C – the radioactive isotope present in only trace amounts. Fluctuations of radiocarbon contribution in Earth’s atmosphere have been mapped so that the date of carbon incorporation in organic material can be accurately determined in a technique called carbon-dating. In a previous paper of the same group, they showed how this principle can be adapted to accurately determine the formation of brain cells in human samples. Nuclear bomb tests during the 1950s and ‘60s raised the levels of radiocarbon with a peak around the mid ‘60s and a decline as the tests were diminished. The isotope found its way into all organic material in the same concentrations as it was present in the atmosphere at the time and therefore also into newly generated human tissues. Thus by measuring the contribution of ¹⁴C relative to the total carbon, it is possible to determine the time the tissue was formed. In their most recent work, they applied this principle to brain biopsies of MS patients.

Oligodendrocytes in potentially remyelinated multiple sclerosis plaques are old (tree trunk) suggesting that preexisting old oligodendrocytes are able to remyelinate (leaves) axons in humans. Illustration by M. Karlén.

During MS episodes, high inflammation in the nervous system causes myelin sheaths protecting neurons to be degraded. Oligodendrocytes are supportive brain cells responsible for producing myelin and mouse models have shown that regeneration of this cell type can enable remyelination in MS plaques during remission periods. Yeung and colleagues set out to use carbon-dating in brain tissue of MS patients collected post mortem to determine the rate of inclusion of new oligodendrocytes in plaques and adjacent normal-appearing white matter, or NAWM.

Analysis of oligodendrocyte DNA showed a reduced level of ¹⁴C in shadow plaques of patients born before the tests compared to normal individuals, pointing towards a lower generation of this cell type in these areas. The group therefore proposes that shadow plaques in humans are places of demyelination, where remyelination is only carried out by old oligodendrocytes or not at all. In line with this result, density of mature oligodendrocytes in the plaques was similar when compared to adjacent NAWM, confirming previous human studies that showed no difference or a decrease in density. This data strengthens the group’s conclusion that oligodendrocyte production in brain plaques of humans suffering from MS is reduced during the disease episode and the remaining oligodendrocytes in the plaques were generated during the healthy period preceding disease onset. Because contrasting studies on animal models have shown possible strong increases in oligodendrocyte generation within plaques, these results underline the importance of direct studies on human material to elucidate relevant biology of MS in humans.

A contrasting analysis of oligodendrocyte generation in NAWM showed a surprising correlation between a high turnover of oligodendrocytes in these regions and aggressive disease. This observation could point to an inherent capacity of the brain to regenerate lost tissue, particularly in times of major injury. Responses to aggressive disease were however not consistent; some patients with aggressive disease did not show this elevated generation of new oligodendrocytes in NAWM. Moreover, it is impossible to draw conclusions about the functionality of these newly generated cells. Still, the observation that regeneration of new mature oligodendrocytes is possible in MS patients with aggressive disease is encouraging and could potentially be exploited in new therapies. Extended research might even reveal molecular ways to activate this hidden potential.

References:

1. Yeung, M. S. Y. et al. Dynamics of oligodendrocyte generation in multiple sclerosis. Nature. (2019) [Epub ahead of print].
2. Spalding, K. L., Bhardwaj, R. D., Buchholz, B. A., Druid, H. & Frisén, J. Retrospective birth dating of cells in humans. Cell 122, 133–143 (2005).
3. Yeung, M. S. et al. Dynamics of oligodendrocyte generation and myelination in the human brain. Cell 159, 766–774 (2014).