The immortal strand hypothesis captures stem cell scientists’ imagination these days. According to Thomas Rando The immortal strand hypothesis posits that the propensity of stem cell compartments to give rise to cancer in later life can be minimized if stem cells, during the process of self-renewal, retain those DNA strands with the fewest mutations acquired during DNA replication. Key concepts of biology are connected by the hypothesis: stem cells, cancer, aging, symmetric and asymetric cell division, DNA replication and replication-induced mutations.
At the SENS3 conference Mike Conboy from Berkeley, who is a former postdoc of Thomas Rando at Stanford gives us some muscle regeneration related data concerning the hypothesis:
|Stem cells dividing, sister chromatids choose fate: old stays, young moves on|
M.J. Conboy, A.O. Karasov, T.A. Rando
Department of Bioengineering, University of California Berkeley, Berkeley, California, USA
Before cells divide, they duplicate macromolecules and organelles. When they divide, sometimes they sort the older versus newer “parts” to the daughter cells. Over 35 years ago Cairns proposed the “Immortal DNA Strand hypothesis”, where the stem daughter cell might retain the older or more “original” strands of DNA and thus limit accumulating errors of replication, while continuing to proliferate for the life of an organism. Originally based on observations in animal and plant cells, this hypothesis has remained largely unknown or unaccepted because of few additional reports, relatively few cells displaying template strand segregation and alternate interpretations of the data. We used sequential pulses of different thymidine analogs to label DNA strands of different ages in the cells in regenerating muscle, in vivo. We observed extraordinarily high frequencies of cells segregating older versus younger DNA to the daughter cells. Furthermore, this DNA inheritance asymmetry correlated with asymmetric cell divisions yielding daughters with divergent fates. Daughter cells inheriting the older templates exhibited a stem-like immature phenotype, whereas daughters inheriting the newer templates showed a more differentiated phenotype. These data provide compelling evidence of the Immortal DNA phenomenon in muscle regeneration and suggest that it may be more common in stem cell self-renewal than previously assumed. We propose that the Immortal DNA hypothesis be revisited as pertains to aging, cancer and development, and suggest implications for the SENS.
Key words: immortal DNA, stem cell template
John Cairns: Cancer and the Immortal Strand Hypothesis
Conboy MJ, Karasov AO, Rando TA: High Incidence of Non-Random Template Strand Segregation and Asymmetric Fate Determination In Dividing Stem Cells and their Progeny PLoS Biol. 2007 May; 5(5)
Rando TA: The immortal strand hypothesis: segregation and reconstruction Cell. 2007 Jun 29;129(7):1239-43. (Figure is from this paper.)
The contrarian view: Lansdorp PM: Immortal strands? Give me a break. Cell. 2007 Jun 29;129(7):1244-7.