Mechanistic Target of Rapamycin Complex 2 Regulation of the Primary Human Trophoblast Cell Transcriptome

Fredrick J Rosario; Amy Catherine Kelly; Madhulika B Gupta; Theresa L Powell; Laura Cox; Thomas Jansson

doi:10.3389/fcell.2021.670980

Mechanistic Target of Rapamycin Complex 2 Regulation of the Primary Human Trophoblast Cell Transcriptome

Front Cell Dev Biol. 2021 Nov 4:9:670980. doi: 10.3389/fcell.2021.670980. eCollection 2021.

Authors

Fredrick J Rosario¹, Amy Catherine Kelly¹, Madhulika B Gupta², Theresa L Powell^{1

3}, Laura Cox⁴, Thomas Jansson¹

Affiliations

¹ Division of Reproductive Sciences, Department of OB/GYN University of Colorado Anschutz Medical Campus, Aurora, CO, United States.
² Children's Health Research Institute and Department of Pediatrics and Biochemistry, University of Western Ontario, London, ON, Canada.
³ Section of Neonatology, Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, CO, United States.
⁴ Section of Molecular Medicine, Department of Internal Medicine, Center for Precision Medicine, Wake Forest School of Medicine, Winston-Salem, NC, United States.

Abstract

Mechanistic Target of Rapamycin Complex 2 (mTORC2) regulates placental amino acid and folate transport. However, the role of mTORC2 in modulating other placental functions is largely unexplored. We used a gene array following the silencing of rictor to identify genes regulated by mTORC2 in primary human trophoblast (PHT) cells. Four hundred and nine genes were differentially expressed; 102 genes were down-regulated and 307 up-regulated. Pathway analyses demonstrated that inhibition of mTORC2 resulted in increased expression of genes encoding for pro-inflammatory IL-6, VEGF-A, leptin, and inflammatory signaling (SAPK/JNK). Furthermore, down-regulated genes were functionally enriched in genes involved in angiogenesis (Osteopontin) and multivitamin transport (SLC5A6). In addition, the protein expression of leptin, VEGFA, IL-6 was increased and negatively correlated to mTORC2 signaling in human placentas collected from pregnancies complicated by intrauterine growth restriction (IUGR). In contrast, the protein expression of Osteopontin and SLC5A6 was decreased and positively correlated to mTORC2 signaling in human IUGR placentas. In conclusion, mTORC2 signaling regulates trophoblast expression of genes involved in inflammation, micronutrient transport, and angiogenesis, representing novel links between mTOR signaling and multiple placental functions necessary for fetal growth and development.

Keywords: gene array; human; maternal-fetal exchange; nutrient sensor; placenta.

Grants and funding

R01 HD068370/HD/NICHD NIH HHS/United States