Extended Data Fig. 8: Modelled ¹⁴C concentration in DNA of oligodendrocytes generated from OPCs in shadow plaques.

a, Measured and modelled data. The levels of atmospheric ¹⁴C before 1955 are indicated by the dotted line. Mean (long line) ± s.d. (short lines). Statistical analyses represent comparison between shadow plaque data (n = 6) and the other groups (model 1–7, see b–h) compared to healthy white matter (**P = 0.0047, two-tailed Mann–Whitney U-test, n = 10). b–h, Measured and modelled data plotted in relation to time and atmospheric ¹⁴C concentration. b, Model 1: the estimated ¹⁴C concentration in mature oligodendrocytes in shadow plaques if assumed to have healthy turnover rate until the death of the patients is similar to healthy white matter oligodendrocytes (red line and red circles in a) and is significantly higher than the measured ¹⁴C levels in mature oligodendrocytes in shadow plaques (in a, **P = 0.002, two-tailed Mann–Whitney U-test, n = 6 and 6). c, d, Models 2 and 3: to reconstitute the observed mature oligodendrocyte density with new oligodendrocytes, it would require OPCs to divide at least four times. If this occurred over the time course from the onset of the disease (model 2; c) or even from 10 years before the first clinical symptoms (model 3; d) until the death of the patient, the resulted modelled ¹⁴C levels were significantly higher than the ¹⁴C levels measured from mature oligodendrocytes in shadow plaques (in a, model 2, **P = 0.002, two-tailed Mann–Whitney U-test, n = 6, model 3, **P = 0.002, two-tailed Mann–Whitney U-test, n = 6). e, f, Models 4 and 5: even with more conservative models that assume all oligodendrocyte replacements occur not throughout the disease course, but early by the proliferation of OPCs at disease onset or before, the modelled ¹⁴C levels still result in higher levels than the measured shadow plaque oligodendrocytes (blue) in some patients (a). g, h, Models 6 and 7: modelled data as above, but with 50% of oligodendrocytes being newly made from OPCs and 50% being old oligodendrocytes. For some patients, the time of disease onset and 10 years before onset occur before the rise of the ¹⁴C atmospheric levels (1955). For these patients, any cell replacement by the proliferation of old OPCs during this period would results in values similar to atmospheric levels. Arrows points to patients with time periods before and disease onsets that overlap with very highly increased atmospheric ¹⁴C levels compared to respective levels at time of birth of the patients, and that the modelled values deviate from the measured rules out these scenarios. The red line depicts genomic DNA ¹⁴C concentrations in oligodendrocytes from healthy subjects. **P < 0.01. See also Supplementary Tables 1, 11 and 12.

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