Development of epithelial and mesenchymal regionalization of the human fetal utero‐vaginal anlagen

Abstract

Literature on the development of the human vagina is abundant; however, contributions concerning the prenatal development of the entire utero-vaginal anlagen (UVA) are rare or carried out in rodents. The primary epithelial characteristics in the adult vagina and uterus are determined during prenatal development and depend on epithelio-mesenchymal stroma interaction; thus an investigation summarizing the spatiotemporal distribution of relevant molecular markers in the entire human UVA will be of current interest. We phenotyped epithelial and mesenchymal characteristics in sagittal sections from 24 female fetuses of 14-34 weeks of gestation and two female newborns by immunostaining with cytokeratins 8, 13, 14 and 17, p63, bcl-2, bmp4, HOX A13, CD31, VEGF, SMA, Pax2 and vimentin. Epithelial differentiation followed a caudal-to-cranial direction in the UVA. Due to the cytokeratin profile of cytokeratins 8, 13 and 14, the characteristics of the different epithelial zones in the UVA could already be recognized in middle-age fetuses. Vaginal epithelium originated from the urogenital sinus in the lower portion and initiated the transformation of vimentin-positive M€ ullerian epithelium in the upper vaginal portion. During prenatal development the original squamo-columnar junction was clearly detectable from week 24 onwards and was always found in the cervical canal. Early blc-2 positivity within the surrounding mesenchyme of the entire vagina including the portio region pointed to an organ-specific mesenchymal influence. Prenatal findings in human specimens clearly show that fornix epithelium up to the squamo-columnar junction is of vaginal M€ ullerian origin, and the cervical epithelium cranial to the squamo-columnar junction is of uterine M€ ullerian origin and includes cells with enough plasticity to transform into squamous epithelium.

New insights into human female reproductive tract development

“…With this caveat, we have re-visited the classic studies of Koff and Bulmer and extended the more recent studies of Fritsch et al by providing detailed high-resolution documentation of human female reproductive tract development (Bulmer, 1957; Fritsch et al, 2012; Fritsch et al, 2013; Koff, 1933). Significantly, through use of immunohistochemistry we have described the dynamic age-dependent changes in the contribution of Müllerian versus UGS epithelium in the development of human vaginal epithelium, which depart markedly from the complete elimination of UGS epithelial cells from vaginal epithelium in mice (Kurita, 2010).…”

“…Various theories have suggested that vaginal epithelium receives contributions from epithelium of the urogenital sinus, Müllerian or Wolffian ducts alone or in combination (Koff, 1933; O’Rahilly, 1977; Forsberg, 1978; Bulmer, 1957). Particularly valuable are the recently published works of Cai and Fritsch et al (Cai, 2009; Fritsch et al, 2012; Fritsch et al, 2013). …”

“…Such findings show that ΔNp63 is critical for vaginal differentiation of Müllerian epithelium (Kurita et al, 2004). The central role of p63 appears to also apply to human vaginal epithelial differentiation (Kurita et al, 2005; Fritsch et al, 2012; Fritsch et al, 2013). …”

“…Most modern investigators access these data via low-resolution copies, making evaluation even more difficult. Fritsch et al recently published in color, but the rather small in size of their published images hampers evaluation (Fritsch et al, 2012; Fritsch et al, 2013). Accordingly, we take this opportunity to review the relevant literature on vaginal epithelial differentiation, to provide large format color images of vaginal epithelial differentiation, and to utilize immunohistochemistry to explore the question of the relative contribution of Müllerian versus urogenital sinus epithelium to human vaginal epithelial differentiation.…”

“…The seminal paper on this topic by Koff appeared in 1933 when the technical state of the art was tissue sections 25 to 100μ thick stained with hematoxylin and eosin (Koff, 1933). From this humble beginning, the field has progressed to elegant epithelial cell lineage tracing to reveal the relative contribution of epithelium of the urogenital sinus (UGS) versus the Müllerian (paramesonephric) ducts to vaginal epithelial development in mice (Kurita, 2010) and immunohistochemical studies in man (Fritsch et al, 2013; Fritsch et al, 2012). The current paper and its two companions (a) review the collective trove on human female reproductive tract development (Bulmer, 1957; Cai, 2009; Forsberg, 1996; Fritsch et al, 2013; Fritsch et al, 2012; Hunter, 1930; Koff, 1933; Konishi et al, 1984; Kurita, 2010; Mutter and Robboy, 2014; O’Rahilly, 1977; 1983; O’Rahilly and Muller, 1992; Reich and Fritsch, 2014; Sinisi et al, 2003; Sulak et al, 2007; Forsberg, 1973), (b) provide new data on the derivation of human vaginal epithelium and (c) highlight the role of differentiation markers and signaling pathways involved in human uterovaginal development.…”