Researchers have developed a new laboratory model grown from stem cells that replicates the human amniotic sac in the first two to four weeks after fertilization.
The structure, which the researchers say is the most advanced and mature amniotic model ever created, could offer new insight into human development and lead to cell products for medical procedures, from burn treatments to cornea reconstruction, the team reported in a study published July 10 in the journal Cell.
The growing human embryo isn’t alone on its developmental journey. “Supporting tissues like the placenta, like the amniotic sac, grow with the embryo and are really important for the embryo’s growth and survival,” said study co-author Silvia Santos, a group leader at the Francis Crick Institute in London.
The amniotic sac is a fluid-filled, biological balloon that cushions and protects the growing embryo. The liquid it contains is thought to be essential for healthy embryo development. But it hasn’t been easy to investigate this interplay between the embryo and its entourage, largely because this stage of development is logistically difficult and ethically fraught to study inside human beings.
Previous attempts at modeling the amniotic sac in the lab were unable to replicate its complex 3D structure, which has two distinct cell layers. In addition, previous models tended to last only a few days, making it harder to get insight into the extended process of development.
By contrast, Santos’ new cell models, called post-gastrulation amnioids (PGAs), can survive in their lab dishes for at least three months and develop to the same degree as a month-old amniotic sac. Remarkably, they grow to a similar size, too — up to about an inch (2.5 centimeters).
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“They are little golf balls,” Santos told Live Science. The PGAs also form the amniotic sac’s distinct two-layer structure.
To achieve this, Santos’ team used a new cell-culture method. They began with embryonic stem cells, which can grow to become any other cell type in the body if nudged with specific signaling molecules. The team exposed these cells to two of these signals, called BMP4 and CHIR. They made sure to space out the signals, adding BMP4 over the first 24 hours of growth, followed by CHIR for another 24 hours.
Then, the researchers left the cells alone in round-bottomed culture dishes. “The rest was complete self-organization,” meaning the maturing stem cells orchestrated their own assembly into a structure, Santos said.
Single cells aggregated in the dishes and formed the distinct two-layered, fluid-filled structure the team had searched for. “This just shows you that these embryonic stem cells have this amazing propensity to specialize and to become everything given the right instructions, which I’m still in awe about,” Santos said.
Armed with their new models, the team set out to answer key questions about how amniotic sacs influence their environment. They wanted to know what genes might be directing cells to turn into PGAs. By interfering with a long list of genes that they suspected might influence cell development, they found that a single gene, GATA3, could convert cells into amniotic sacs without any other signals.
GATA3 codes for a transcription factor — a protein that turns other genes on or off. Santos and her team showed that two of the genes GATA3 regulates are BMP4 and CHIR, the same genes their culture protocol had involved.
To explore how the amniotic sac may influence nearby cells, they mixed their PGAs with additional stem cells that hadn’t been nudged to become any particular cell type. Left on their own, these cells would have continued to exist in their unspecialized state. But next to the PGAs, they changed into a host of other “extraembryonic” cell types, showing that the amniotic sac was capable of driving the transformation of cells around it.
Santos and her team are now exploring possible applications for their new system. Amniotic sacs have antimicrobial and anti-inflammatory properties, and people who have had elective C-sections can opt to donate their amniotic sacs for use as transplant tissue in burn treatments or cornea repairs. These donated materials can be difficult to standardize, Santos said, but PGAs could theoretically provide a reliable source of these desired cells.
Yi Zheng, an assistant professor in biomedical and chemical engineering at Syracuse University who was not involved in the study, said further tests would be required to see whether PGAs could provide clinically useful materials for such procedures.
He added that mature, non-stem cells can be transformed back into stem cells called induced pluripotent stem cells (iPSCs). Perhaps, Zheng said, iPSCs converted into PGAs could be particularly useful for medical applications, in part because you could use a patient’s own cells to generate them.
Better models of the amniotic sac could also help researchers understand why this critical structure sometimes malfunctions. Some congenital disorders — meaning those babies are born with — are tied to differences in the size or content of the sac prior to birth, and Santos said the PGAs could help explain that link.
“I’m extremely excited about the potential of these little structures,” she concluded.
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