Non-Random Chromosome Segregation in Stem Cells

Autor: Thomas A. Rando, Ariela O Karasov, Michael J. Conboy
Jazyk: angličtina
Rok vydání: 2007
Předmět:
Zdroj: PLoS Biology, Vol 5, Iss 5, p e102 (2007)
PLoS Biology
ISSN: 1545-7885
1544-9173
Popis: Decades ago, the “immortal strand hypothesis” was proposed as a means by which stem cells might limit acquiring mutations that could give rise to cancer, while continuing to proliferate for the life of an organism. Originally based on observations in embryonic cells, and later studied in terms of stem cell self-renewal, this hypothesis has remained largely unaccepted because of few additional reports, the rarity of the cells displaying template strand segregation, and alternative interpretations of experiments involving single labels or different types of labels to follow template strands. Using sequential pulses of halogenated thymidine analogs (bromodeoxyuridine [BrdU], chlorodeoxyuridine [CldU], and iododeoxyuridine [IdU]), and analyzing stem cell progeny during induced regeneration in vivo, we observed extraordinarily high frequencies of segregation of older and younger template strands during a period of proliferative expansion of muscle stem cells. Furthermore, template strand co-segregation was strongly associated with asymmetric cell divisions yielding daughters with divergent fates. Daughter cells inheriting the older templates retained the more immature phenotype, whereas daughters inheriting the newer templates acquired a more differentiated phenotype. These data provide compelling evidence of template strand co-segregation based on template age and associated with cell fate determination, suggest that template strand age is monitored during stem cell lineage progression, and raise important caveats for the interpretation of label-retaining cells.
Author Summary For each chromosome, the complementary DNA strands consist of a “younger” strand synthesized during the most recent round of DNA replication and an “older” strand synthesized during a previous cell division. When the strands separate to serve as templates for DNA synthesis during a subsequent round of replication, the two sister chromatids formed thus differ in terms of the template strand age. The “immortal strand hypothesis” predicts that a stem cell is capable of distinguishing between chromatids based on template age: when it divides, the self-renewing daughter will inherit the chromatids with the older templates, whereas the daughter destined to differentiate will inherit those with the newer templates. However, in vivo evidence in support of this hypothesis has been sparse. By labeling newly synthesized DNA in sequential divisions of stem/progenitors during muscle regeneration, we observed that almost half of the dividing cells sorted their chromatids based on template age. The more stem-like daughter inherited chromatids with older templates, and the more differentiated daughter inherited chromatids with younger templates. We propose that this phenomenon is a characteristic of asymmetrically dividing stem cells and their progeny.
Analysis of the segregation of older and younger DNA template strands in proliferating muscle stem cells provides compelling evidence of co-segregation based on template age and associated with cell fate determination.
Databáze: OpenAIRE
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