Distinct Subsets of Stromal Cells Confined to Unique Microenvironments in Human Endometrium Throughout the Menstrual Cycle

Abstract

Human endometrial stroma exhibits rather uniform morphology throughout the endometrium. However, predecidualization develops characteristically around vessels and subsequently around glands and under surface epithelium, demonstrating existence of regional differences among stromal cells. Immunoreactivity of stromal cells in endometrial tissues from various phases of the menstrual cycle, as elucidated by employing monoclonal antibodies to cytokeratin, vimentin, very late antigen-1 (VLA-1), Ber-EP4, and HLA-DR, revealed presence of phenotypically distinct subsets of stromal cells confined to unique microenvironments throughout the menstrual cycle. All stromal cells strongly expressed vimentin and weakly expressed cytokeratin. However, Ber-EP4 positive stromal cells were distinctly confined around glands and to the subluminal regions of the surface epithelium. The intervening stromal cells were Ber-EP4 negative. The HLA-DR positive stromal cells were characteristically present in three different locations: around glands and under surface epithelium, around blood vessels and around HLA-DR positive lymphoid cells. From all antigens studied, only expression of VLA-1 in the stromal cells showed a characteristic change throughout the menstrual cycle. Stromal cells in the proliferative and early secretory phases were VLA-1 negative. However, VLA-1 characteristically developed initially in the HLA-DR positive cells around vessels and then in HLA-DR/Ber-EP4 positive cells around glands and under surface epithelium. Eventually, all stromal cells in the upper functionalis expressed VLA-1 in the late secretory phase of the menstrual cycle. These data underscore a heterogeneity in stromal cells not exemplified by their morphology. Also, they provide a basis for understanding the differences that the stroma exhibits in morphologic and functional differentiation throughout the menstrual cycle.