Abstract
BackgroundRecent studies have identified stem/progenitor cells in human and mouse uterine epithelium, which are postulated to be responsible for tissue regeneration and proliferative disorders of human endometrium. These progenitor cells are thought to be derived from Müllerian duct (MD), the primordial female reproductive tract (FRT).Methodology/Principal FindingsWe have developed a model of human reproductive tract development in which inductive neonatal mouse uterine mesenchyme (nMUM) is recombined with green fluorescent protein (GFP)-tagged human embryonic stem cells (hESCs); GFP-hESC (ENVY). We demonstrate for the first time that hESCs can be differentiated into cells with a human FRT epithelial cell phenotype. hESC derived FRT epithelial cells emerged from cultures containing MIXL1+ mesendodermal precursors, paralleling events occurring during normal organogenesis. Following transplantation, nMUM treated embryoid bodies (EBs) generated epithelial structures with a typical MD phenotype that expressed the MD markers PAX2, HOXA10. Functionally, the hESCs derived FRT epithelium responded to exogenous estrogen by proliferating and secreting uterine-specific glycodelin A (GdA).Conclusions/SignificanceThese data show nMUM can induce differentiation of hESC to form the FRT epithelium. This may provide a model to study early developmental events of the human FRT.
Highlights
During embryogenesis, the mesoderm emerges from the primitive streak and gives rise to coelomic epithelium
We grafted ovariectomized mice with two types of controls; embryoid bodies (EBs) formed in the absence of growth factors (n = 4) or EBs treated with BMP4/ACTIVIN A (n = 4), growth factors known to induce human embryonic stem cells (hESCs) to differentiate towards mesendoderm, an obligate intermediate during female reproductive tract (FRT) development
We detected ciliated simple columnar epithelium in each graft derived from both the non-growth factor treated (n = 2) and growth factor treated EB/neonatal mouse uterine mesenchyme (nMUM) recombinant tissues (n = 30) (Figure 1B, C). Grafts derived from these samples were smaller than those arising from EBs formed in the absence of nMUM and/or growth factors, (Figure S1A), consistent with previous studies showing that differentiated hESC had reduced the potential for teratoma formation [5,17]
Summary
The mesoderm emerges from the primitive streak and gives rise to coelomic epithelium. The regenerative capacity of the endometrium has been attributed to a small population of resident stem/progenitor cells Our laboratory discovered these cells in both the stroma and epithelium of the adult human and murine uterus [1,2,3]. Recent studies have identified stem/progenitor cells in human and mouse uterine epithelium, which are postulated to be responsible for tissue regeneration and proliferative disorders of human endometrium. These progenitor cells are thought to be derived from Mullerian duct (MD), the primordial female reproductive tract (FRT)
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