Notably, confocal imaging and consequent 3D renderings of optical sections of endometrial glands revealed increased glandular complexity of the human uterus compared with mouse. Understanding the 3D structure of the endometrium has contributed to our current perception of embryo implantation and postnatal glandular morphogenesis in mice. These studies implicitly assume the endometrial glandular organisation to be blind-ending single tubes, a hypothesis yet to be confirmed. Tanaka et al explored the clonality of epithelial cells by analysing DNA extracted from individual endometrial glands using the X-linked androgen receptor gene as an indirect marker of non-random X chromosome inactivation, and reported on the clonal constitution of glandular cells and luminal epithelium (LE) Kim et al proposed that cell divisions and ancestry may be surreptitiously recorded by identifying replication errors that naturally accumulate in a clock-like manner during aging based on the hypothesis that all daughter cells originate from a common ancestor. Attempts have been made previously to investigate human endometrial epithelial cell lineages utilising two methods. However, the precise three-dimensional (3D) anatomical micro-architectural organisation of the human endometrial glandular mucosa is unknown. Epithelial stem cells are postulated to reside in the terminal ends of the blind-ended single-tubular endometrial glands at the endometrial/myometrial interface, analogous to the structural organisation of intestinal crypts. The current consensus envisages that human endometrial stem cells are responsible for this efficient regeneration. The endometrium is a highly regenerative tissue that undergoes more than 400 monthly cycles of proliferation and sloughing under the influence of ovarian hormones during a woman's lifetime. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland. These novel findings provide insight into the efficient and scar-less regenerative potential of the human endometrium. Vertical tracking of mutated clones showed that at least one stem-cell population resides in the basalis glands. The existence of a multipotent endometrial epithelial stem cell capable of regenerating the entire complement of glandular lineages was demonstrated by in vivo lineage tracing, using naturally occurring somatic mitochondrial DNA mutations as clonal markers. We demonstrate that some non-branching, single, vertical functionalis glands originate from a complex horizontally interconnecting network of basalis glands. Utilising fixed samples from patients, we have studied the three-dimensional (3D) micro-architecture of the human endometrium. The current consensus postulates endometrial glands to have a single-tubular architecture, where multi-potential stem cells reside in the blind-ending glandular-bases. Regular menstrual shedding and repair of the endometrial functionalis is unique to humans and higher-order primates.
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