Reversal of gene dysregulation in cultured cytotrophoblasts reveals possible causes of preeclampsia.
During human pregnancy, a subset of placental cytotrophoblasts (CTBs) differentiates into cells that aggressively invade the uterus and its vasculature, anchoring the progeny and rerouting maternal blood to the placenta. In preeclampsia (PE), CTB invasion is limited, reducing placental perfusion and/or creating intermittent flow. This syndrome, affecting 4%-8% of pregnancies, entails maternal vascular alterations (e.g., high blood pressure, proteinuria, and edema) and, in some patients, fetal growth restriction. The only cure is removal of the faulty placenta, i.e., delivery. Previously, we showed that defective CTB differentiation contributes to the placental component of PE, but the causes were unknown. Here, we cultured CTBs isolated from PE and control placentas for 48 hours, enabling differentiation and invasion. In various severe forms of PE, transcriptomics revealed common aberrations in CTB gene expression immediately after isolation, including upregulation of SEMA3B, which resolved in culture. The addition of SEMA3B to normal CTBs inhibited invasion and recreated aspects of the PE phenotype. Additionally, SEMA3B downregulated VEGF signaling through the PI3K/AKT and GSK3 pathways, effects that were observed in PE CTBs. We propose that, in severe PE, the in vivo environment dysregulates CTB gene expression; the autocrine actions of the upregulated molecules (including SEMA3B) impair CTB differentiation, invasion and signaling; and patient-specific factors determine the signs.
The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, UCSF, San Francisco, California 94143-0665, USA.
Yan
Y
Zhou
Matthew J
MJ
Gormley
Nathan M
NM
Hunkapiller
Mirhan
M
Kapidzic
Yana
Y
Stolyarov
Victoria
V
Feng
Masakazu
M
Nishida
Penelope M
PM
Drake
Katherine
K
Bianco
Fei
F
Wang
Michael T
MT
McMaster
Susan J
SJ
Fisher
D000818:Animals; D019556:COS Cells; D002454:Cell Differentiation; D002465:Cell Movement; D002642:Chick Embryo; D002522:Chlorocebus aethiops; D058543:Class Ia Phosphatidylinositol 3-Kinase / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D006801:Humans; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000378:metabolism; D039942:Neuropilin-1 / Q000235:genetics / Q000378:metabolism; D039943:Neuropilin-2 / Q000235:genetics / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D010920:Placenta / Q000473:pathology; D011225:Pre-Eclampsia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011247:Pregnancy; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D039961:Semaphorins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D059467:Transcriptome; D014327:Trophoblasts / Q000378:metabolism* / Q000502:physiology; D042461:Vascular Endothelial Growth Factor A / Q000502:physiology; D051176:beta Catenin / Q000378:metabolism
D008562:Membrane Glycoproteins; D039943:Neuropilin-2; D012333:RNA, Messenger; C409766:SEMA3B protein, human; D039961:Semaphorins; D042461:Vascular Endothelial Growth Factor A; D051176:beta Catenin; C581308:neuropilin-2, human; D039942:Neuropilin-1; D058543:Class Ia Phosphatidylinositol 3-Kinase; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3