Embryos implant in 3D womb lining models

Both natural human embryos and stem cell-based embryo models (SCBEMs) have been observed implanting in cultured models of the human endometrial lining.

Three studies, published simultaneously, had similar findings. One study was conducted by an international team led by researchers at the Babraham Institute in Cambridge and at Stanford University in California, and was published in Cell. Another study was the result of a collaboration between researchers at the Chinese Academy of Sciences in Beijing and the University of Texas, and also appeared in Cell. A third study, published in Cell Stem Cell, was conducted mainly at Shandong University in China.

'Understanding embryo implantation and embryo development just after implantation has significant clinical relevance as these stages are particularly prone to failure,' said Dr Peter Rugg-Gunn, from the Babraham Institute, who led the first study. 'In particular, the high rate of implantation failure represents one of the main limiting factors for IVF success.'

Human conception can occur either inside the body (when it is achieved naturally) or outside the body (when it is achieved via IVF). However, an embryo resulting from conception must implant inside the human body, in order for a pregnancy to be established. This means that the implantation process cannot be observed directly, and is therefore difficult to study.

The three new studies used somewhat different approaches to overcome this difficulty and create three-dimensional models of the human endometrium, but all three studies made use of two specific cell types – stromal cells and epithelial cells. Cells of these types were obtained from endometrial biopsies, or from hysterectomy samples. They were then cultured – sometimes, organoids were created as an intermediate step – and finally they were combined, in such a way as to mimic the structure of the endometrial lining.

In the Babraham/Stanford-led study, the researchers studied implantation of both natural human embryos (donated by IVF patients) and blastoids (a type of SCBEM that emulates the blastocyst stage of embryo development). The natural embryos continued to develop following implantation, but in accordance with UK law and international guidelines, the experiments were terminated before embryo development exceeded 14 days from fertilisation.

As for the blastoids, some of these were also able to implant into the endometrial model surface. The implanted blastoids proceeded to develop cell types and structures that would be expected in natural embryos, until they exhibited features consistent with natural embryos that have developed for 12 days following fertilisation.

In the Beijing/Texas study, implantation was compared between endometrial models created from the tissues of healthy patients (who had become pregnant following IVF), and endometrial models created from the tissues of IVF patients who had experienced implantation failure at least three times (following transfer of at least four good-quality embryos in total). In the latter case, natural human embryos were much less likely to attach to the surface of the endometrial models. The researchers then considered the effects of drugs on their system, to see which drugs seemed to improve implantation rates.

'These studies represent important advances in our understanding of human embryo implantation, which is a critical and complex aspect of our early biology,' Professor Robin Lovell Badge – chair of trustees at PET, and also a developmental biologist at the Frances Crick Institute in London – told BioNews (see BioNews 1321). 'There is substantial overlap between the three studies, which adds considerable robustness to their findings.'

Several of the researchers involved in the studies have been keen to stress that the focus of their work is the study of embryo implantation, rather being than a step toward ectogenesis (the development to viability of an organism outside a host organism). None of the endometrial models in these studies contained vascular tissue, meaning that the models could not support the blood flow that would be necessary to sustain a placenta.

The International Society for Stem Cell Research (ISSCR) last year updated its Guidelines for Stem Cell Research and Clinical Translation, adding a prohibition on 'culture in an artificial in vitro system designed to develop SCBEMs to viability (ie, ectogenesis)' (see BioNews 1302). Dr Rugg-Gunn was a member of the ISSCR Embryo Models Working Group, which worked on updating those Guidelines, and was also a member of the Working Group that drafted the UK's Code of Practice for the Generation and Use of Human Stem-Cell-Based Embryo Models (see BioNews 1246).