Brain matter matters : renewal in the human brain

Many cells have a shorter life span than the organism itself and are continuously being replaced. However, for many cell types in the human body it is still largely unknown whether they turn over at all once development is complete. The work presented in this thesis focuses on understanding the occurrence of cell renewal in the human brain and how it may affect brain function. We further explore if the ability of cell renewal may also be affected in the diseased brain. To investigate cell turnover in the human brain we used a methodology developed in the Frisén laboratory. The developed strategy takes the advantage of the integration of the 14C (carbon-14) isotope, produced from the nuclear bomb tests during the Cold War, into genomic DNA, to determine the age of cells in humans.

In Paper I we assessed the dynamics of oligodendrocyte generation and myelination in the human brain. We found that the number of oligodendrocytes in the corpus callosum is established in childhood and remains constant thereafter. We revealed that myelin is continually exchanged, whereas white matter oligodendrocytes are remarkably stable with an annual exchange of 1 in 300 oligodendrocytes. This suggests that myelin modulation in humans may be carried out by mature oligodendrocytes. Moreover, we also found different kinetics of oligodendrocyte generation and turnover between gray and white matter, with a longer period of oligodendrocyte generation and higher turnover rate throughout life in gray matter, showing the possibility of de novo myelination in the sparsely myelinated cortex. However, how generation kinetics of the oligodendrocyte population may change under pathological conditions such as in the demyelination disease multiple sclerosis has been unknown.

In Paper II we investigated the oligodendrocyte generation dynamics in multiple sclerosis patients. We observed no induced generation of oligodendrocytes in normal appearing white matter, except in a subsets of multiple sclerosis patients with a very aggressive progression of the disease. We also revealed that oligodendrocytes in remyelination lesions were old in multiple sclerosis patients, showing that existing and not new oligodendrocytes are regenerating myelin in multiple sclerosis.

In Paper III we examined the extent of postnatal olfactory bulb neurogenesis in humans. We report that the olfactory bulb neurons are almost as old as the individuals, establishing that there is very limited, if any, postnatal neurogenesis in the human olfactory bulb.

Together the findings presented in this thesis highlight a conceptual and fundamental difference in human brain plasticity compared to other mammals.

List of scientific papers

I. Yeung M.S., Zdunek S., Bergmann O., Bernard S., Salehpour M., Alkass K., Perl S., Tisdale J., Possnert G., Brundin L., Druid H., Frisén J. (2014). Dynamics of oligodendrocyte generation and myelination in the human brain. Cell. 159;766-774.
https://doi.org/10.1016/j.cell.2014.10.011

II. Yeung M.S., Djelloul M., Steiner E., Bernard S., Salehpour M., Possnert G., Brundin L., Frisén J. Remyelination by old oligodendrocytes in multiple sclerosis. [Manuscript]

III. Bergmann O., Liebl J., Bernard S., Alkass K., Yeung, M.S., Steier P., Kutschera W., Johnson L., Landen M., Druid H., Spalding K., Frisén J. (2012). The age of olfactory bulb neurons in humans. Neuron. 74;634-639.
https://doi.org/10.1016/j.neuron.2012.03.030