Interleukin-15 deficient rats have reduced osteopontin at the maternal-fetal interface

Kelly J Baines; Michelle S Klausner; Violet S Patterson; Stephen J Renaud

doi:10.3389/fcell.2023.1079164

Interleukin-15 deficient rats have reduced osteopontin at the maternal-fetal interface

Front Cell Dev Biol. 2023 Apr 20:11:1079164. doi: 10.3389/fcell.2023.1079164. eCollection 2023.

Authors

Kelly J Baines¹, Michelle S Klausner¹, Violet S Patterson¹, Stephen J Renaud^{1

2}

Affiliations

¹ Department of Anatomy and Cell Biology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada.
² Children's Health Research Institute, Lawson Health Research Institute, London, ON, Canada.

Abstract

Introduction: Uterine Natural Killer (NK) cells are the predominant immune cells within the decidua during early pregnancy. These cells are thought to regulate aspects of decidualization and placental development, but their functions remain poorly characterized, especially in species with deeply invading trophoblasts such as humans and rats. Interleukin-15 (IL-15) is a cytokine required for NK cell development and survival. IL-15 mutant (IL15Δ/Δ) rats lack NK cells and exhibit altered placental development with precocious trophoblast invasion. In this study, we profiled gene expression differences between wild-type and IL15Δ/Δ implantation sites to reveal candidate factors produced by uterine NK cells that may regulate placentation and trophoblast invasion. Methods: Clariom S gene expression profiling was performed using implantation sites collected from pregnant wild-type and IL15Δ/Δ rats on gestational day 9.5. Levels and localization of perforin and osteopontin in implantation sites from wild-type and IL15Δ/Δ rats were further analyzed. The effect of osteopontin on the invasive capacity of rat trophoblasts was evaluated using Matrigel-based Transwell assays. Results: There were 257 genes differentially expressed between wild-type and IL15Δ/Δ implantation sites on gestational day 9.5, including decreased expression of various NK cell markers in IL15Δ/Δ rats, as well as Spp1, which encodes osteopontin. In wild-type rats, osteopontin was present within the decidua basalis and adjacent to the primitive placenta, and osteopontin colocalized with the NK cell marker perforin. Osteopontin was also detectable in uterine glands. Conversely, in IL15Δ/Δ rats, osteopontin and perforin were not readily detectable in the decidua despite robust osteopontin levels in uterine glands. Neutralization of osteopontin in media conditioned by cells isolated from the decidua decreased invasion of rat trophoblasts, suggesting that reduced levels of osteopontin are unlikely to account for the precocious trophoblast invasion in IL15Δ/Δ rats. Conclusion: Osteopontin is expressed by NK cells at the maternal-fetal interface in rats and may contribute to modulation of trophoblast invasion.

Keywords: decidua; interleukin-15; natural killer cells; osteopontin; placenta; trophoblast.

Grants and funding

Experiments in this study were supported by the Canadian Institutes of Health Research (PJT152983 and PJT180483) to SR. VP is supported by a fellowship from the Children’s Health Research Institute.