Counting human somatic cell replications: Methylation mirrors endometrial stem cell divisions

Abstract

Cell proliferation may be altered in many diseases, but it is uncertain exactly how to measure total numbers of divisions. Although it is impossible to count every division directly, potentially total numbers of stem cell divisions since birth may be inferred from numbers of somatic errors. The idea is that divisions are surreptitiously recorded by random errors that occur during replication. To test this ''molecular clock'' hypothesis, epigenetic errors encoded in certain methylation patterns were counted in glands from 30 uteri. Endometrial divisions can differ among women because of differences in estrogen exposures or numbers of menstrual cycles. Consistent with an association between mitotic age and methylation, there was an age-related increase in methylation with stable levels after menopause, and significantly less methylation was observed in lean or older multiparous women. Methylation patterns were diverse and more consistent with niche rather than immortal stem cell lineages. There was no evidence for decreased stem cell survival with aging. An ability to count lifetime numbers of stem cell divisions covertly recorded by random replication errors provides new opportunities to link cell proliferation with aging and cancer.cancer ͉ endometrium ͉ molecular clock

DNA methylation within the normal colorectal mucosa is associated with pathway-specific predisposition to cancer

“…'Type A' methylation was actually highest in elderly normal patients, whereas those with colorectal adenomatous lesions had significantly lower levels of 'type A' methylation. The positive correlation between 'type A' methylation and age supports the concept that 'type A' methylation reflects the mitotic 'age' of a tissue, an epigenetic record of cell turnover (Ahuja et al, 1998;Ahuja and Issa, 2000;Issa et al, 2001;Kim et al, 2005). Thus, 'type A' methylation, rather than being a prelude to cancer (Issa et al, 1994;Ahuja et al, 1998;Ahuja and Issa, 2000), might represent a component of 'normal' aging.…”

Human uterine stem/progenitor cells: their possible role in uterine physiology and pathology

“…Conversely, abandoned are epigenetic changes emerging from more mature descendant cells presumably present in the functionalis endometrium when these cells are lost during menstruation. Kim et al (2005) analysed the methylation patterns found in individual glands derived from cycling and atrophic human endometrium mathematically, substantiating the idea that there exists a stem cell niche in an individual gland. Furthermore, an undetermined number of stem/progenitor cells with long life span, but not a single stem cell, may be present in each niche (Kim et al 2005).…”

“…Investigation of methylation patterns in individual endometrial glands is one of the retrospective approaches for studying the activity of endometrial stem/progenitor cells (Kim et al 2005). A 'cellular history' encoded by epigenetic variations in individual glands reflects the methylation patterns arising from stem/progenitor cells, because such epigenetic changes are thought to be transmitted to daughter cells.…”

Attributes of adult stem cells

“…are also found in surface epithelial cells that are not menstruated in the mouse [125]. SP cells are found in the stratum basalis of human endometrial glands [125] and, based upon DNA methylation patterns, individual glands, like intestinal crypts, appear to be populated by multiple stem cells [126].…”