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Decidual NK Cells Alter In Vitro First Trimester Extravillous Cytotrophoblast Migration: A Role for IFN-¹

Yuxiang Hu^*,¶, Jan P. Dutz^,¶, Colin D. MacCalman^*,¶, Paul Yong^,,¶, Rusung Tan^,¶ and Peter von Dadelszen^2,*,¶

^* Department of Obstetrics and Gynaecology, Department of Medicine, Department of Pathology and Laboratory Medicine, and Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada; and ^¶ Child and Family Research Institute, Centre for Healthcare Innovation and Improvement, and Programs in Infection and Immunity and Reproductive Health, Vancouver, British Columbia, Canada

Abnormal placentation results in either inadequate (consequences: recurrent miscarriage, intrauterine growth restriction, and preeclampsia) or overzealous (consequences: placenta accreta, increta, and percreta) placentation. NK cells dominate in first trimester decidua and probably control extravillous cytotrophoblast (EVT) invasion. We examined this interaction in a novel way, using NK cells and villous explants from concordant first trimester pregnancies cocultured using a new collagen (two-dimensional) model of placentation. Decidual NK (dNK) cells exerted contact-independent inhibition of normal cytotrophoblast migration, associated with changes in the cytotrophoblast expression of metalloproteases-2 and -9, and plasminogen activator inhibitor-1. dNK cells did not affect EVT proliferation and apoptosis, and cell column formation. dNK cell effects were partially reversed by neutralizing Abs against IFN-. We provide ex vivo human evidence of a direct role for dNK in modulating EVT differentiation as they form columns and then migrate from anchoring villi.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This study was funded by a Pilot Grant from the Infection and Immunity Program, Child and Family Research Institute. Y.H. is funded by grants from the Canadian Institutes for Health Research, from whom P.v.D. receives salary support. C.D.M. and P.v.D. receive salary support from the Child and Family Research Institute. P.v.D. and R.T. receive salary support from the Michael Smith Foundation for Health Research.

² Address correspondence and reprint requests to Dr. Peter von Dadelszen, Department of Obstetrics and Gynaecology, University of British Columbia, 2H30-4500 Oak Street, Vancouver, British Columbia V6H 3N1, Canada. E-mail address: pvd{at}cw.bc.ca

³ Abbreviations used in this paper: dNK, decidual NK; EVT, extravillous cytotrophoblast; TIMP, tissue inhibitor of metalloprotease; MTS, 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium; PAI, plasminogen activator inhibitor; CM, dNK-derived conditioned medium; HF, hollow fiber; IQR, interquartile range; MMP, matrix metalloprotease; uPA, urokinase-type protease activator.

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