L4: Intercellular communications during implantation Flashcards
What are the crucial requirements for embryo implantation?
- Window of implantation (days 19 - 21)
- Healthy embryo at blastocyst
- Receptive endometerium -> effective communication between mother and embryo at time of implantation)
Define infertility:
- Unable to get pregnant after 1 year of unprotected sex
Incidence of infertility in UK:
- 1 in 6 couples
In ART, what is the proportion of failure due to implantation failure?
- 70%
What are the three key stages of embryo implantation?
- (Hatching)
- Apposition
- Adhesion (tissues express adhesion molecule, pinopodes)
- Invasion (of endometrial stroma by trophectoderm layer of blastocyst)
Effect of estrogen in endometrial stroma:
- Oestrogen induces expression of…
- IL-11 -> Promotion of decidualisation (alongside activin A)
- IGF1
Role of HB-EGF in endometrial stroma:
- Promotes glandular secretion
- Endometrial cellular proliferation
- Decidualisation
Role of TGFB on embryo competence:
- Increases invasiveness
- Promotes adhesion of trophobast
- Promotes pre- and post-implantation embryo development
Role of TGFB in uterine receptivity:
- Promotes proliferation
- Decidualisation
- Promotes implantation
- Remodelling of endometrium
Effect of COX-2 expression by blastocyst on endometrium:
- Catalyses prostaglandin production (E)
- -> Increased vascular permeability
- -> Promotes implantation
- -> Promotes adhesiveness of uterine lining (endometrium)
Endocrine: What factors do ovarian estrogen and progesterone affect:
- GFs -> proliferation
- TFs -> Transcriptional programmes
- Lipid mediators -> tissue interactions
- Cytokines -> Immune response
- Cell cycle regulators -> quality control, cell death
How does estrogen and progesterone communicate with the cell?
- Via estrogen receptors (alpha and beta) or PR-A, -B
- Expressed in epithelium and stroma of human endometrium
- ER: Interaction with site-specific DNA and coregulatory proteins
- PR: activation regulates transcriptional programmes for implantation
Outline the modes of effect of hCG in the early embryo:
- Secreted by early embryo, commonly found in women’s blood and urine throughout pregnancy (testing)
- Autocrine effect on trophoblast
- Paracrine effect on maternal ovary and endometrium
Outline the communication by cytokines in early embryo:
- IL-1 system: IL-1alpha and -beta, 2x receptors (type I, II), receptor antagonist
- Act as first line of response of blastocysts to a receptive endometrium -> induces second wave of cytokines/GFs
Communication by IGFs in receptive endometrium:
- System: 2x ligands, 2x receptors, 6 BPs
- IGFBP-1 modulates mitogenic and metabolic effects of IGF1, 2
- Localised to predecidual stromal cells in late secretory-phase endometrium and decidual cells during pregnancy
- IGF2: Secreted by trophoblasts, inhibits IGFBP-1 (negative feedback)
- IL-1B: Inhibits IGFBP-1
-> Clarify!
MUC-1 and its role:
- Highly polymorphic mucin-like protein
- Acts as a barrier to implantation -> removed prior to implantation
Osteopontin and its role:
- Upregulated in receptive endometrium
- Strongly upregulated by progesterone in mid-secretory, receptive phase
- Various forms
- Binds to cell surface receptors, signals through adhesion proteins and coreceptors (IGF1R, EGFR, FGRF)
Define extracellular vesicles:
- Membrane enclosed nano-sized vesicle discharge by a cell that carries cargo between cell
- Cargoes: DNA, RNA, proteins
What are the three classes of EV?
- Apoptotic bodies
- Microvesicles
- Exosomes
How do EVs act in tumours?
- Carrying CS marker, signalling molecules, oncogenic proteins, nucleic acids -> horizontal transfer to target cells
- Conditioning microenvironment to support tumour growth
Cardiovascular function of EVs:
- Maintaining normal cardiac function
- Released by cardiomyocytes
- Also contribute to cardiovascular disease
EVs in implantation:
- Secreted by both trophectoderm and endometrium (ideal case)
- Involved in processes across all stages of process
- Key method for paracrine signalling (e.g. quality control of blastocyst)
- e.g. hCG, IL-1B secretion by embryo
Evidence for quality control via EVs (bovine oviductal epithelial cells):
- EVs released by individually cultured pre-implantation embryos can alter gene expression in BOECs
- Transcriptional response of BOECs varied by embryo quality
- -> Potential for quality sensing role in vivo
- -> Applications in non-invasive quality assessment in clinics
