Identification of Novel Trophoblast Invasion-Related Genes: Heme Oxygenase-1 Controls Motility via Peroxisome Proliferator-Activated Receptor γ

Abstract

Invasion of cytotrophoblasts (CTBs) into uterine tissues is essential for placental development. To identify molecules regulating trophoblast invasion, mRNA signatures of purified villous (CTB, poor invasiveness) and extravillous trophoblasts (EVTs) (high invasiveness) isolated from first trimester human placentae and villous explant cultures, respectively, were compared using GeneChip analyses yielding 991 invasion/migration-related transcripts. Several genes involved in physiological and pathological cell invasion, including A disintegrin and metalloprotease-12, -19, -28, as well as Spondin-2, were up-regulated in EVTs. Pathway prediction analyses identified several functional modules associated with either the invasive or noninvasive trophoblast phenotype. One of the genes that was down-regulated in the invasive mRNA pool, heme oxygenase-1 (HO-1), was selected for functional analyses. Real-time PCR analyses, Western blotting, and immunofluorescence of first trimester placentae and differentiating villous explant cultures demonstrated down-regulation of HO-1 in invasive EVTs as compared with CTBs. Modulation of HO-1 expression in loss-of as well as gain-of function cell models (BeWo and HTR8/SVneo, respectively) demonstrated an inverse relationship of HO-1 expression with trophoblast migration in transwell and wound healing assays. Importantly, HO-1 expression led to an increase in protein levels and activity of the nuclear hormone receptor peroxisome proliferator activated receptor (PPAR) gamma. Pharmacological inhibition of PPARgamma abrogated the inhibitory effects of HO-1 on trophoblast migration. Collectively, our results demonstrate that gene expression profiling of EVTs and CTBs can be used to unravel novel regulators of cell invasion. Accordingly, we identify HO-1 as a negative regulator of trophoblast motility acting via up-regulation of PPARgamma.

Protective effects of adiponectin against renal ischemia‐reperfusion injury via prostacyclin‐PPARα‐Heme oxygenase‐1 signaling pathway

“…Recently it has been shown that HO-1 can induce PPAR transcription activity (Bilban et al, 2009). In the present study we used two different methods; PPARa-siRNA in vitro and PPARa knockout mice in vivo, to confirm that the induction of HO-1 expression in the renal tubular cells is dependent on PPARa (Fig.…”

Epithelial-mesenchymal transition during extravillous trophoblast differentiation

“…49 In normal placentae, ZO-1 and occludin are localized to the syncytium and villous trophoblast, but are not expressed in EVT. 76 The present literature as well as published mRNA expression data, 77 which are available at GEO profiles (accession number GDS3523[ACCN]), also suggests that many features of EMT such as downregulation of junction proteins (CLDN1/4, OCLN, MPP5, ZO1), and upregulation of EMT-associated and -promoting genes (ITGA5, ITGB1, FSP1, SPARC, HSP47, SNAIL, TCF-4, FN1) occur during EVT differentiation of cytotrophoblasts (CTB) (Fig. 2).…”

Human HLA-G+ extravillous trophoblasts: Immune-activating cells that interact with decidual leukocytes

“…In contrast to two recent studies (26,36), the VT and EVT preparations were highly purified and used directly after isolation without in vitro culture to minimize transcriptional changes that may occur with cell culture. Interestingly, the signature for TACSTD2+ VT (27) did not match the transcriptional signature for EGFR1+ VT and may indicate that these are distinct subtypes of VT.…”