Human embryo models could unlock the “black box” of early development
Researchers have used naïve pluripotent stem cells to create an embryo model that looks and acts like a natural human embryo. They say it’s an ethical way of gaining a better understanding of embryonic development that may lead to new avenues of research into birth defects and infertility.
Between eight and 10 days after fertilization, an egg travels through the fallopian tubes and burrows into the uterus wall, marking the beginning of pregnancy (medically speaking). After implantation, the embryo continues to grow and develop. It’s at this time that the major organs and body systems are forming, making the developing embryo vulnerable to birth defects.
Studying embryos to gain a greater understanding of their complex development is difficult for ethical and technical reasons. However, researchers from the Weizmann Institute of Science in Israel may have come up with a way to do it.
“The drama is in the first month; the remaining eight months of pregnancy are mainly lots of growth,” said Jacob Hanna, corresponding author of the study. “But that first month is still largely a black box. Our stem-cell-derived human embryo model offers an ethical and accessible way of peering into this box. It closely mimics the development of a real human embryo, particularly the emergence of its exquisitely fine architecture.”
The researchers built on their previous experience creating synthetic mouse embryo models made solely from stem cells. As with their prior research, they began with pluripotent stem cells, which have the ability to differentiate into many – but not all – cell types. But the researchers reprogrammed the pluripotent stem cells to revert to an even earlier state, known as the naïve state, making them capable of differentiating into any type of cell.
They divided the naïve pluripotent stem cells into three groups. Those intended to develop into an embryo were left as is. Cells in the other two groups were treated only with chemicals – that is, genetically unmodified – to turn on certain genes intended to cause them to differentiate into one of three tissue types needed to sustain the embryo. Soon after being mixed, the cells clumped together, and about 1% of them self-organized into complete, embryo-like structures.
“An embryo is self-driven by definition; we don’t need to tell it what to do – we must only unleash its internally encoded potential,” Hanna said. “It’s critical to mix in the right kinds of cells at the beginning, which can only be derived from naïve stem cells that have no developmental restrictions. Once you do that, the embryo-like model itself says, ‘Go!’”
The embryo-like structures developed normally outside of a womb for eight days, reaching a developmental stage equivalent to day 14 in human embryonic development, the point at which natural embryos acquire the structures that enable them to start developing bodily organs.
The researchers found that their embryo models were structurally similar to natural human embryos seen in old textbooks. They even observed the cells that make human chorionic gonadotropin (hCG), the hormone used in pregnancy testing, were present and active. Applying secretions from these cells to a home pregnancy test saw it register a positive result.
“Many failures of pregnancy occur in the first few weeks, often before the woman even knows she’s pregnant,” said Hanna. “That’s also when many birth defects originate, even though they tend to be discovered much later. Our models can be used to reveal the biochemical and mechanical signals that ensure proper development at this early stage and the way in which that development can go wrong.”
Their study has already opened up a new direction for future research. The researchers found that if the embryo is not enveloped by placenta-forming cells correctly at day three – which corresponds to day 10 in natural embryonic development – its internal structures fail to develop properly.
“An embryo is not static,” Hanna said. “It must have the right cells in the right organization, and it must be able to progress – it’s about being and becoming. Our complete embryo model will help researchers address the most basic questions about what determines its proper growth.”
The researchers say their embryo model could reveal the cause of birth defects and types of infertility, as well as leading to new technologies for growing transplant tissues and organs. And it could offer a way of performing experiments, such as determining the effect of drugs on development, that don’t involve live embryos.
The study was published in the journal Nature.
Source: Weizmann Institute of Science