title: PreImplantation factor (PIF*) promotes embryotrophic and neuroprotective decidual genes: effect negated by epidermal growth factor.
abstract: BACKGROUND
  Intimate embryo-maternal interaction is paramount for pregnancy success post-implantation. The embryo follows a specific developmental timeline starting with neural system, dependent on endogenous and decidual factors. Beyond altered genetics/epigenetics, post-natal diseases may initiate at prenatal/neonatal, post-natal period, or through a continuum. Preimplantation factor (PIF) secreted by viable embryos promotes implantation and trophoblast invasion. Synthetic PIF reverses neuroinflammation in non-pregnant models. PIF targets embryo proteins that protect against oxidative stress and protein misfolding. We report of PIF's embryotrophic role and potential to prevent developmental disorders by regulating uterine milieu at implantation and first trimester.
  
  
  METHODS
  PIF's effect on human implantation (human endometrial stromal cells (HESC)) and first-trimester decidua cultures (FTDC) was examined, by global gene expression (Affymetrix), disease-biomarkers ranking (GeneGo), neuro-specific genes (Ingenuity) and proteins (mass-spectrometry). PIF co-cultured epidermal growth factor (EGF) in both HESC and FTDC (Affymetrix) was evaluated.
  
  
  RESULTS
  In HESC, PIF promotes neural differentiation and transmission genes (TLX2, EPHA10) while inhibiting retinoic acid receptor gene, which arrests growth. PIF promotes axon guidance and downregulates EGF-dependent neuroregulin signaling. In FTDC, PIF promotes bone morphogenetic protein pathway (SMAD1, 53-fold) and axonal guidance genes (EPH5) while inhibiting PPP2R2C, negative cell-growth regulator, involved in Alzheimer's and amyotrophic lateral sclerosis. In HESC, PIF affects angiotensin via beta-arrestin, transforming growth factor-beta (TGF-β), notch, BMP, and wingless-int (WNT) signaling pathways that promote neurogenesis involved in childhood neurodevelopmental diseases-autism and also affected epithelial-mesenchymal transition involved in neuromuscular disorders. In FTDC, PIF upregulates neural development and hormone signaling, while downregulating genes protecting against xenobiotic response leading to connective tissue disorders. In both HESC and FTDC, PIF affects neural development and transmission pathways. In HESC interactome, PIF promotes FUS gene, which controls genome integrity, while in FTDC, PIF upregulates STAT3 critical transcription signal. EGF abolished PIF's effect on HESC, decreasing metalloproteinase and prolactin receptor genes, thereby interfering with decidualization, while in FTDC, EGF co-cultured with PIF reduced ZHX2, gene that regulates neural AFP secretion.
  
  
  CONCLUSIONS
  PIF promotes decidual trophic genes and proteins to regulate neural development. By regulating the uterine milieu, PIF may decrease embryo vulnerability to post-natal neurodevelopmental disorders. Examination of PIF-based intervention strategies used during embryogenesis to improve pregnancy prognosis and reduce post-natal vulnerability is clearly in order.
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, Yale Women and Children's Center for Blood Disorders, Yale University School of Medicine, 333 Cedar St, P.O. Box 208063, New Haven, CT 06520, USA.
authors.forename: Christina M
authors.initials: CM
authors.lastname: Duzyj
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, Yale Women and Children's Center for Blood Disorders, Yale University School of Medicine, 333 Cedar St, P.O. Box 208063, New Haven, CT 06520, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Paidas
authors.affiliation: GeneGo Inc., A Thomson Reuters Business, 5901 Priestly Drive Suite 200, Carlsbad, CA 92008, USA.
authors.forename: Lellean
authors.initials: L
authors.lastname: Jebailey
authors.affiliation: Department of Obstetrics and Gynecology, Reproductive Biology Unit, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Jing Shun
authors.initials: JS
authors.lastname: Huang
authors.affiliation: Society for the Investigation of Early Pregnancy, 1697 Lark Lane, Cherry Hill, NJ 08003, USA ; BioIncept LLC (PIF Proprietary), 1697 Lark Lane, Cherry Hill, NJ 08003, USA.
authors.forename: Eytan R
authors.initials: ER
authors.lastname: Barnea
keywords: Embryogenesis; Neural development; Neural disease; Preimplantation factor (PIF); Uterine environment