Gastrulation is the first phase in the human body design. Not birth, marriage, or death, but gastrulation is the most significant period of your life.
It marks the beginning of the process by which a basic sheet of cells develops into all the tissues that make up the body, including the neurons, blood, circulatory, and structural tissues like muscle and bone.
But since it is impossible to investigate this in the lab without using growing embryonic tissue, we haven’t actually been able to research the process in people.
Scientists working with materials at UNSW Sydney have now shown that human pluripotent stem cells may go through a process in the lab resembling gastrulation, in which cells start differentiating into distinct cell types far earlier than happens in nature.
For an embryo growing in the womb, gastrulation happens on day 14. However, in a dish in a lab at UNSW’s Kensington campus, Scientia Associate Professor Kris Kilian oversaw an experiment in which a gastrulation-like event was triggered two days after culturing human stem cells in a unique biomaterial that, it turned out, set the conditions to mimic this stage of embryo development.
Gastrulation is the most important stage in human body design.
It marks the beginning of the process by which a basic sheet of cells develops into all the tissues that make up the body, including the neurons, blood, circulatory, and structural tissues like muscle and bone.
“But,” adds A/Prof. Kilian, “we haven’t really been able to study the process in humans because you can’t study this in the lab without taking developing embryonic tissue.”
“So it’s really exciting that we were able to see this happening in vitro.”
The finding, published today in the journal Advanced Science, has implications for cell therapy, targeted medication development, and CRISPR gene-editing technology, among other potential medical applications.
Your life’s defining moment
According to developmental scientist Lewis Wolpert, “It is not birth, marriage or death, but gastrulation which is truly the most important time in your life.”
The crucial developmental stage known as gastrulation occurs when a mass of undifferentiated cells take the initial steps on a lengthy trip in the womb toward the creation of a human being. This is one of the reasons why IVF embryos can’t be worked on after 14 days, when gastrulation starts to happen.
According to A/Prof Kilian, due to clear ethical limitations, it has been challenging to examine this process in people up to this point.
“Controlling gastrulation using materials alone will provide an entirely new way for studying human development,” he adds.
“We currently can’t do this because embryo research beyond 14 days is often viewed as unethical, and it’s currently impossible in vivo because you’d need to observe an embryo in a pregnant human mother.”
But while mice and zebrafish can be used as models to study gastrulation, and other researchers have induced similar events in the lab using chemicals like growth factors, this is the first time that culture conditions alone have caused gastrulation outside of a human body.
“Our method could lead to a new approach to mimic human embryogenesis outside of a person,” adds A/Prof Kilian.
CRISPR gene splicing and miniature organs
The UNSW team’s ability to trigger gastrulation in “synthetic” embryos may one day be used in medicine to make body tissue or even tiny organs that are tailored to a patient’s unique genetic makeup. Stem cells are already being used to create these so-called “organoids,” which are hardly visible to the human eye, for medical studies, such as evaluating the efficacy of various medications. However, the procedure needs chemicals, which is time-consuming and costly, to drive the cells into producing differentiated organ tissue.
According to A/Prof. Kilian, regulating gastrulation by stimulating what occurs naturally solely using hydrogel materials might be a speedier and more affordable alternative.
“The thing that really excites us about this is the potential to make therapeutically useful cells much faster and more reproducible,” adds A/Prof. Kilian.
“Our method could provide a way to initiate ‘organogenesis’ – with an array of hundreds of well-defined cell aggregates in a single well – leading to faster and more well-defined structures that could then be turned into brain, liver, gut, potentially any solid organ tissue.
“This approach could also revolutionise drug development including RNA and CRISPR/Cas9 approaches by providing a more reproducible way to mimic human tissue in a lab. For instance, you could make an organoid from a patient’s cells, then test therapies aimed at correcting mutations or restoring function.”
Hydrogel homes are ideal
The key to the laboratory success of the UNSW team lies in the structure of the culture into which the stem cells were implanted. Defined zones are created throughout a hydrogel using a method developed from the semiconductor sector so that cells may adhere to them. The soft gel that resembles the surface of a human uterus in conjunction with the geometric confinement encourages the cells to initiate gastrulation-like activities.
“We discovered that if you take pluripotent stem cells and you put them in a very confined and soft environment, it’s akin to what the cells might experience in a mother’s uterus,” adds A/Prof. Kilian.
“That viscoelastic, soft, squishy material gives them just enough cues that they initiate this gastrulation-like process all on their own.”
This is very different from what labs usually do now, which is to use growth factors and chemical supplements to force a type of gastrulation process on hard plastic or glass dishes.
“Unsurprisingly, previous research culturing stem cells on glass or plastic have failed to recapitulate the signals that happen in a body. But using our soft substrates mimicking embryonic tissue, we can coax the cells to spatially organise and begin the early morphogenesis that could ultimately create a person.”
Although the team has identified the circumstances that mimic the first stage of gastrulation, A/Prof. Kilian issues a warning that it doesn’t seem to go much farther.
“We can’t make a person this way,” he adds.
“This method only demonstrates the early, but very crucial stage in development. The impact lies in being able to study this all-important stage of human development, and to use the generated structures for developing therapies.”
Discovery often involves serendipity
As with most important scientific discoveries, it was a happy accident that led to this one. When the scientists put some stem cells onto the hydrogel substrate, they weren’t specifically trying to induce gastrulation.
The findings astonished the study’s lead author, Dr. Pallavi Srivastava.
“Initially I was trying to get stem cells to attach to our hydrogels and planned to differentiate them in the conventional way,” she explains.
“The difference between cells cultured on glass and those on our gels was very striking. I remember thinking, ‘wow, something is going on here. I need to investigate’. This led to a big shift in my project, and ultimately this exciting discovery.”
The researchers hope to find out more about how their discovery can help by learning how materials can guide embryogenesis and other processes. A/Prof. Kilian says that this discovery is exciting, but that more work needs to be done to help the processes that are similar to gastrulation make tissues that are useful.
“This is really the first step in what we hope is a platform technology for producing useful tissue models. Triggering gastrulation is not enough – now we need to provide other signals to keep differentiation going.”
A/Prof. Kilian says that finding the next set of material signals could make it possible to make almost any solid tissue for research and to make useful cell types for regenerative medicine.
“Considering pluripotent stem cells can now be generated from blood or tissue samples, the future is wide open for regenerating tissues and organs from a patient’s own cells.”
Source: 10.1002/advs.202203614
Image Credit: Getty