HB-EGF-loaded nanovesicles enhance trophectodermal spheroid attachment
and invasion
Abstract
The ability of trophectodermal cells (outer layer of the embryo) to
attach to the endometrial cells and subsequently invade the underlying
matrix are critical stages of embryo implantation during successful
pregnancy establishment. Extracellular vesicles (EVs) have been
implicated in embryo-maternal crosstalk, capable of reprogramming
endometrial cells towards a pro-implantation signature and phenotype.
However, challenges associated with EV yield and direct loading of
biomolecules limit their therapeutic potential. We have previously
established generation of cell-derived nanovesicles (NVs) from human
trophectodermal cells (hTSCs) and their capacity to reprogram
endometrial cells to enhance adhesion and blastocyst outgrowth. Here, we
employed a rapid NV loading strategy to encapsulate potent implantation
molecules such as HB-EGF (NVHBEGF). We show these loaded NVs elicit
EGFR-mediated effects in recipient endometrial cells, activating kinase
phosphorylation sites that modulate their activity (AKT S124/129, MAPK1
T185/Y187), and downstream signalling pathways and processes (AKT signal
transduction, GTPase activity). Importantly, they enhanced target cell
attachment and invasion. The phosphoproteomics and proteomics approach
highlight NVHBEGF-mediated short-term signalling patterns and long-term
reprogramming capabilities on endometrial cells which functionally
enhance trophectodermal-endometrial interactions. This proof-of-concept
study demonstrate feasibility in enhancing the potency of NVs in the
context of embryo attachment and establishment.