FUNCTIONAL REGULATION OF HUMAN TROPHOBLAST DIFFERENTIATION

The human trophoblast differentiates from proximal cell column cytotro phoblasts into two lineages: a villous phenotype that results in cell fusion and formation of syncytium and an extravillous phenotype that a dopts an invasive behavior and displays cell surface markers of an end othelial cell. Both phenotypes develop spontaneously in in vitro cultu red cytotrophoblasts, but there is a clear gestational regulation by u nknown genetic and/or maternal environmental factors that results in f irst trimester villous cytotrophoblasts entering the invasive pathway and term villous cytotrophoblasts entering the syncytial pathway. No g enetic factors are known that induce the invasive pathway. First trime ster cytotrophoblasts are induced to enter the invasive pathway by act ivin A, LIF and IL-IP but inhibited from differentiating in this direc tion by TGF beta 1, TGF beta 3, glucocorticoids and hypoxia. Term vill ous cytotrophoblasts are stimulated by EGF, EGF-II, IGFBP-1, alpha 1 b eta 1 integrin (laminin receptor) and hypoxia. Term villous cytotropho blasts are stimulated to form a syncytium by EGF, GM-CSF, CSF-1, dexam ethasone, hCG, fibronectin, collagen I and PL48 and inhibited by TGF b eta 1. As well, there is evidence that TNF alpha and interferon gamma induce and EGF inhibits apoptosis, This provides a mechanism for troph oblast turnover and renewal. Further research will be likely to uncove r additional genetic, cytokine, extracellular matrix and physicochemic al factors that regulate this complex process. (C) 1998 Elsevier Scien ce Ireland Ltd. All rights reserved.