In vitro and in vivo analysis of cellular origin of cervical squamous metaplasia

We have previously shown that cultured normal human endocervical cells (HENs) form epithelium resembling squamous metaplasia in vivo. To analyze the cellular origin of squamous metaplasia, the cytokeratin and mucin expression and morphological features of HENs in monolayer cultures and in implants beneath the skin of nude mice were examined. Primary HENs had two distinct morphological phenotypes in vitro pleomorphic epithelial cells and keratinocytelike cells. Using a panel of monoclonal antibodies for various cytokeratins (CKs), we observed that the pleomorphic cells, which were the primary outgrowths, expressed CK7 and CK18 and produced mucin, suggesting their origin to be the mucosecretory columnar cells (CCs) of the endocervix. Keratinocytelike cells were observed in proximity of the CC-like cells after a few days of HEN culture. Interestingly, these cells were homogeneously negative for CK7 expression, as for native reserve cells (RCs), and homogeneously positive for CK13 expression with the antibody that is specific for RCs. During early passages, the culture consisted mostly of the RC-like keratinocytelike cells, and in the late passages, the CC-like cells were predominant. HEN implants in nude mice morphologically formed epithelia similar to immature squamous metaplasia and showed variable CK18 expression. Moreover, they showed homogeneous CK13 expression throughout all layers and expressed mucin and CK7 in the suprabasal cells. The possibility that the HEN culture was originally a mixed population of CCs and RCs, that we failed to detect, cannot be eliminated. Our results support the more likely view that the endocervical simple epithelia, which form squamous metaplasia, are bipotential cells and undergo differentiation readily and reversibly to give rise to CC-like and RC-like cells in culture.