The use of reconstructed assembloids, multimodal single cell sequencing and nanosensor development to study human implantation and pregnancy loss.

Objective

Human reproductive failure affects one in six couples globally and is a serious global socio-economic concern. Human pregnancy requires implantation of an embryo into the endometrium- yet many unknown or deregulated factors may prevent implantation from occurring. Without understanding the root cause, treating reproductive failure often becomes a guessing game. Most implantation-related events remain uncharted territory, making implantation a true ‘black box’ in biology. The central questions to be addressed in this ERC-proposal, are, firstly how does the human endometrium sense embryos and, secondly how is this selection influenced by the maternal uterine microenvironment. Understanding the molecular and cellular mechanisms underlying these maternal-embryonic interactions has been challenging due to practical and ethical limitations, as well as a lack of reliable in vitro models. To address this, I have recently derived three-dimensional (3D) “sensing-organoids” that closely mimics the human endometrium in vivo. Combined with next-generation single-cell sequencing (NGS), live-cell calcium influx measurements, multi-CRISPR/Cas9 genome editing and delivery of ivt-mRNA; we propose to (I) integrate maternal-embryonic-phenotypic-proteo-genomic signatures to stratify the risk of implantation failure; (II) reveal to what extent individual embryonic exosomes provide competency clues to the mother and (III) to monitor embryo health using a miniature “micro-cradle” nanosensor. From the breakthroughs from this project, we are poised on the cusp of a new set of profound ground-breaking discoveries. The novel methods and approaches developed herein will accelerate scientific knowledge in all applied medical fields that will open new avenues for both the individual and society at large.