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Endocrinology Vol. 138, No. 9 3976-3986
Copyright © 1997 by The Endocrine Society

ARTICLES

Activin Is a Local Regulator of Human Cytotrophoblast Cell Differentiation1

Isabella Caniggia, Stephen J. Lye2 and James C. Cross3

Program in Development and Fetal Health, Samuel Lunenfeld Research Institute, Mount Sinai Hospital (I.C., S.J.L., J.C.C.), and Departments of Obstetrics and Gynaecology (S.J.L., J.C.C.), Pediatrics (I.C.), Physiology (S.J.L.), and Molecular and Medical Genetics (J.C.C.), University of Toronto, Toronto, Ontario, M5G 1X5, Canada

Address all correspondence and requests for reprints to: Dr. James Cross, Program in Development and Fetal Health, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto, Ontario M5G 1X5 Canada. E-mail: cross{at}mshri.on.ca

Cytotrophoblast cells of the first trimester placenta are highly invasive when removed from villi and cultured in vitro. In vivo, however, only selected cytotrophoblast cells break through the overlying syncytiotrophoblast to form cytotrophoblast columns and ultimately invade the endometrium. To explore the role of paracrine growth factors in regulating cytotrophoblast development, we cultured explants of first trimester chorionic villi in vitro. Both activin and inhibin, as well as the activin binding protein follistatin, are produced by various trophoblast cells throughout pregnancy. We found that addition of activin-A, but not inhibin-A, stimulated the outgrowth of cytotrophoblast cells into the surrounding matrix. This outgrowth was characteristic of that observed in extravillous cytotrophoblast cells in vivo; it was accompanied by cell division within the proximal region of the cytotrophoblast outgrowth, synthesis of fibronectin, as well as the expression of markers characteristic of invasive cytotrophoblast cells, human leukocyte antigen-G and matrix metalloproteinase (MMP)-9. Activin also specifically induced the early expression of MMP-2 within villous cytotrophoblast cells. Addition of the activin binding protein, follistatin, blocked all of the effects of exogenous activin. The morphological and biochemical effects of activin were similar to those observed when signaling of endogenous transforming growth factor-ß was blocked. Interestingly, the latter effects were also reversed by the addition of follistatin. These data suggest that activin plays a local role in promoting cytotrophoblast column formation, likely by regulating the differentiation of villous cytotrophoblast into extravillous cytotrophoblast cells.




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