page 721) report evidence for asymmetric segregation of the oldest DNA during neural stem cell proliferation.
According to the immortal strand hypothesis, which was first proposed in the mid-1970s, stem cells actively retain the oldest DNA during asymmetric cell divisions. That DNA should, statistically speaking, contain fewer replication-induced errors than DNA resulting from more rounds of replication. While tantalizing for its logic, the hypothesis has been controversial, and numerous studies have failed to find evidence for it.
Working with mouse neural stem cells, the authors labeled cells with BrdU and then looked at how the DNA segregated. When populations of cells were labeled, dispersed into single cells, and allowed to proliferate, they gave rise to neurospheres that frequently contained a few BrdU-labeled cells. The retention of the label after numerous divisions suggested that labeled DNA was asymmetrically segregated to just a limited number of cells, rather than evenly distributed as would be expected if the chromosomes were randomly sorted.To see whether this interpretation was correct, the team watched clones form under the microscope. A single cell was labeled with BrdU during one division. Subsequent imaging showed evidence of asymmetric segregation of the BrdU-labeled DNA in 6 out of 15 lines.
Similar experiments failed to show evidence for asymmetric retention of older DNA in mouse embryonic stem cells or a fibroblast cell line derived from mouse embryos. Thus, neural stem cells may be particularly fussy about their DNA relative to other stem cell types. If it is true that only some stem cells follow the immortal strand hypothesis, that might explain why previous experiments did not find evidence supporting the hypothesis.
The authors are now turning to other stem cell systems in mice and other metazoans to see whether they can replicate their findings in different contexts—and try to convince still-skeptical colleagues that the immortal strand hypothesis holds value.