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Mol. Hum. Reprod. Advance Access published online on April 22, 2008
Molecular Human Reproduction, doi:10.1093/molehr/gan018
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© The Author 2008. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

IFN-gamma-mediated extravillous trophoblast outgrowth inhibition in first trimester explant culture: a role for insulin-like growth factors

Yuxiang Hu, MD, MSc1,4, Rusung Tan, MD, DPhil2,4, Colin D. MacCalman, PhD1,4, Genevieve Eastabrook, MD1,4, Se-Hyung Park, MSc1,4, Jan P. Dutz, MD3,4 and Peter von Dadelszen, MBChB, DPhil1,4

1Departments of Obstetrics and Gynaecology, University of British Columbia, 2H30-4500 Oak Street, Vancouver, BC V6H 3N1, Canada 2Pathology and Laboratory Medicine, University of British Columbia, 2H30-4500 Oak Street, Vancouver, BC V6H 3N1, Canada 3Dermatology and Skin Science, University of British Columbia, 2H30-4500 Oak Street, Vancouver, BC V6H 3N1, Canada 4 the Child and Family Research Institute, University of British Columbia, 2H30-4500 Oak Street, Vancouver, BC V6H 3N1, Canada

Address for correspondence Dr Peter von Dadelszen, 2H30-4500 Oak Street, Vancouver, BC V6H 3N1, Canada e-mail: pvd{at}cw.bc.ca

Pre-eclampsia is often associated with inadequate cytotrophoblast invasion and remodelling of the uterine spiral arteries. Examining a first trimester, two-dimensional in vitro explant culture model which mimics in vivo placentation, including trophoblast column formation and extravillous cytotrophoblast (EVT) migration, we previously suggested that excessive maternal decidual natural killer cell IFN-{gamma} limits EVT migration. Types-1 and -2 insulin-like growth factor (IGF-1, IGF-2) are trophic for EVT, act through their surface receptors, IGFR-1 and IGFR-2, and are regulated by the IGF-binding proteins (IGFBPs). Could the observed IFN-{gamma} mediated inhibition of EVT outgrowth and migration be related to either expression changes of IGF-1 or IGF-2, their receptors, their binding proteins, or apoptosis? Using the two-dimensional explant culture model, we examined the effect of IFN-{gamma} exposure on IGF-1 and -2, IGFR-1 and -2, IGFBPs, and apoptosis. IFN-{gamma} relatively increased IGF-1 and -2 secretion. In EVT, IFN-{gamma} decreased IGFR-2, but not IGFR-1, expression. IGBP-2, -3 and -4 production were not influenced by IFN-{gamma}. IFN-{gamma} induced trophoblast apoptosis measured by the highly sensitive M30 neo-epitope, but not caspase 3 activity, in conditioned medium and EVT cell lysates. The observed IFN-{gamma}-mediated EVT migration inhibition may occur through the downregulation of IGFR-2 and subtle induction of EVT apoptosis.

Key Words: villous explant culture/IFN-{gamma}/insulin-like growth factors (IGFs)/insulin-like growth factor receptors (IGFRs)/insulin-like growth factor binding proteins (IGFBPs)

Submitted on August 30, 2007; resubmitted on March 11, 2008; accepted on April 9, 2008.


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