Early human embryo models generated from skin cells

An international team of scientists led by Melbourne’s Monash University has generated a model of a human embryo from skin cells — a breakthrough that is expected to revolutionise research into the causes of early miscarriage, infertility and the study of early human development. Their work has been published in the journal Nature.

A few days after an egg has been fertilised, it develops into a blastocyst. This is a spherical structure made up of an outer layer of cells surrounding a fluid-filled cavity that contains a mass of embryonic cells. However, our understanding of early human embryonic development has been limited by a lack of appropriate models. Human blastocysts donated to research following IVF have provided insights, but their availability and use is limited. Mouse blastocyst-like structures called blastoids have meanwhile been produced in the laboratory, modelling several aspects of early development in mice, but the generation of similar blastoids from human cells has not previously been reported.

A team led by Professor Jose Polo, from the Monash Biomedicine Discovery Institute and the Australian Regenerative Medicine Institute, has now reprogrammed human fibroblasts — the main cell type found in connective tissue — to produce three-dimensional models of the human blastocyst in the laboratory, which they called ‘iBlastoids’ (induced blastoids). The scientists found that iBlastoids model the overall architecture of blastocysts and are capable of giving rise to pluripotent and trophoblast stem cells. They were also able to model several aspects of the early stage of implantation. They note, however, that an iBlastoid should not be considered as an equivalent to a human blastocyst, as it is not generated using an egg or sperm and has limited ability to develop beyond the first few days.

The Polo Lab succeeded in generating the iBlastoids using a technique called ‘nuclear reprogramming’, which allowed them to change the cellular identity of human skin cells that — when placed in a 3D ‘jelly’ scaffold known as an extracellular matrix — organised themselves into blastocyst-like structures. Jia Ping Tan, a PhD student in the Polo Lab and co-first author on the study, said, “We are really amazed to discover skin cells can be reprogrammed into these 3D cellular structures resembling the blastocyst.”

iBlastoids are morphologically and molecularly similar to human blastocysts, modelling their overall genetics and architecture — including an inner cell mass-like structure made up of epiblast-like cells, surrounded by an outer layer of trophectoderm-like cells and a cavity resembling the blastocoel. In human embryos the epiblast goes on to develop into the embryo proper, while the trophectoderm becomes the placenta.

“iBlastoids are not completely identical to a blastocyst,” Prof Polo noted. “For example, early blastocysts are enclosed within the zone pellucida, a membrane derived from the egg that interacts with sperm during the fertilisation process and later disappears. As iBlastoids are derived from adult fibroblasts, they do not possess a zona pellucida.”

With the ability to model the biology of early human embryos in the laboratory, without the use of actual embryos, iBlastoids should provide a significant breakthrough for the future study of early human development, including infertility and miscarriage. Some miscarriages can be caused by early-stage human embryos failing to implant or failing to progress at the time of implantation; a process that takes place in the first two weeks after conception, when women do not even know they are pregnant. These ‘silent’ miscarriages are likely to represent a significant proportion of the total number of miscarriages that occur.

According to Prof Polo, the generation of iBlastoids provides a model system that will enable insights into this early stage of pregnancy. In the past, the only other way to study these first days has been through the use of difficult-to-obtain blastocysts obtained from IVF procedures.

“iBlastoids will allow scientists to study the very early steps in human development and some of the causes of infertility, congenital diseases and the impact of toxins and viruses on early embryos — without the use of human blastocysts and, importantly, at an unprecedented scale, accelerating our understanding and the development of new therapies,” Prof Polo said.

In similar research, also published in Nature, scientists from the University of Texas Southwestern Medical Center have developed a 3D culture strategy that allowed them to generate blastocyst-like structures, which they term ‘human blastoids’, from human pluripotent stem cells. The human blastoids resembled human blastocysts in their morphology, size, cell number and composition of different cell lineages. Human blastoids are able to generate embryonic and extraembryonic stem cells and can self-organise into structures with features of peri-implantation human embryos; the authors emphasise, however, that human blastoids are not equivalent to human blastocysts and are unable to give rise to a viable embryo.

The publication of the two studies comes as the International Society for Stem Cell Research is about to release guidelines for research on modelling human embryos in vitro following 2017 and 2018 reports on the generation of mouse ‘blastoids’ in vitro by UK and Netherlands scientists, as well as advances in the generation of human stem cells that replicate aspects of early embryonic development. It is not known whether the new guidelines will reference the Polo study, which is the first to produce an integrated stem cell model that closely mimics key fate and spatio-temporal decisions made by the early human embryo. The Society has, however, stated, in a paper published in Stem Cell Reports in February 2020, that “if such models could be developed for the early human embryo, they would have great potential benefits for understanding early human development, for biomedical science, and for reducing the use of animals and human embryos in research. However, guidelines for the ethical conduct of this line of work are at present not well defined.”

Image caption: PhD student Jia Ping Tan, Professor Jose Polo and Dr Xiaodong (Ethan) Liu.

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