Evidence
Evidence for the immortal DNA strand hypothesis has been found in various systems. One of the earliest studies by Karl Lark et al. demonstrated co-segregation of DNA in the cells of plant root tips. Plant root tips labeled with tritiated thymidine tended to segregate their labeled DNA to the same daughter cell. Though not all the labeled DNA segregated to the same daughter, the amount of thymidine-labeled DNA seen in the daughter with less label corresponded to the amount that would have arisen from sister-chromatid exchange. Later studies by Christopher Potten et al. (2002), using pulse/chase experiments with tritiated thymidine, found long-term label-retaining cells in the small intestinal crypts of neonatal mice. These researchers hypothesized that long-term incorporation of tritiated thymidine occurred because neonatal mice have undeveloped small intestines, and that pulsing tritiated thymidine soon after the birth of the mice allowed the 'immortal' DNA of adult stem cells to be labeled during their formation. These long-term cells were demonstrated to be actively cycling, as demonstrated by incorporation and release of BrdU.
Since these cells were cycling but continued to contain the BrdU label in their DNA, the researchers reasoned that they must be segregating their DNA using an immortal DNA strand mechanism. Joshua Merok et al. from the lab of James Sherley engineered mammalian cells with an inducible p53 gene that controls asymmetric divisions. BrdU pulse/chase experiments with these cells demonstrated that chromosomes segregated non-randomly only when the cells were induced to divide asymmetrically like adult stem cells. These asymmetrically dividing cells provide an in vitro model for demonstration and investigation of immortal strand mechanisms.
Scientists have strived to demonstrate that this immortal DNA strand mechanism exists in vivo in other types of adult stem cells. In 2005, Gilbert Smith published evidence that a subset of mouse mammary epithelial cells could retain DNA label and release DNA label in a manner consistent with the immortal DNA strand mechanism. Soon after, scientists from the laboratory of Derek van der Kooy showed that mice have neural stem cells that are BrdU-retaining and continue to be mitotically active. Asymmetric segregation of DNA was shown using real-time imaging of cells in culture. In 2006, scientists in the lab of Shahragim Tajbakhsh presented evidence that that muscle satellite cells, which are proposed to be adult stem cells of the skeletal muscle compartment, exhibited asymmetric segregation of BrdU-labelled DNA when put into culture. They also had evidence that demonstrated BrdU release kinetics consistent with an immortal DNA strand mechanism were operating in vivo, using juvenile mice and mice with muscle regeneration induced by freezing.
These experiments supporting the immortal strand hypothesis, however, are not conclusive. While the Lark experiments demonstrated co-segregation, the co-segregation may have been an artifact of radiation from the tritium. Although Potten identified the cycling, label-retaining cells as adult stem cells, these cells are difficult to identify unequivocally as adult stem cells. While the engineered cells provide an elegant model for co-segregation of chromosomes, studies with these cells were done in vitro with engineered cells. Some features may not be present in vivo or may be absent in vitro. In May 2007 evidence in support of the Immortal DNA Strand theory was discovered by Michael Conboy et al., using the muscle stem/satellite cell model during tissue regeneration, where there is tremendous cell division during a relatively brief period of time. Using two BrdU analogs to label template and newly synthesized DNA strands, they saw that about half of the dividing cells in regenerating muscle sort the older "Immortal" DNA to one daughter cell and the younger DNA to the other. In keeping with the stem cell hypothesis, the more undifferentiated daughter typically inherited the chromatids with the older DNA, while the more differentiated daughter inherited the younger DNA.
Experimental evidence against the immortal strand hypothesis is sparse. In one study, researchers incorporated tritiated thymidine into dividing murine epidermal basal cells. They followed the release of tritiated thymidine after various chase periods, but the pattern of release was not consistent with the immortal strand hypothesis. Although they found label-retaining cells, they were not within the putative stem cell compartment. With increasing lengths of time for the chase periods, these label-retaining cells were located farther from the putative stem cell compartment, suggesting that the label-retaining cells had moved. However, finding conclusive evidence against the immortal strand hypothesis has proven difficult.
Read more about this topic: Immortal DNA Strand Hypothesis
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